Ann Hematol (1991) 63:119-121
Annals of
Hematology 9 Springer-Verlag 1991
Clinicopathologic Conference Acquired bleeding disorder in a patient with congenital factor VII deficiency J. M. J. M. Zijlmans, E. Briet, L . H . van Hulsteyn, J.C. Kluin-Nelemans, and R. Bieger University Hospital Leiden, Department of Hematology,Building 1: C2-R, P.O. Box 9600, 2300 RC Leiden, The Netherlands
Presentation o f case
A 27-year-old man was admitted to the hospital because of spontaneous muscular and subcutaneous hematomas. He had been well until six days before when he experienced pain in the right and left gluteal regions. Although he had played soccer the day before, he could not remember a specific trauma. He had played soccer weekly for many years without bleeding complications. For relief of pain he took one tablet of acetylsalicylic acid that same day. Four days before admission he noticed blue discolorations on his buttocks and thighs. He visited his family physician who found subcutaneous and muscular hemorrhages, prescribed ketoprofen for the pain and performed some hemostatic tests. The thrombocyte count was 220x 109/1, bleeding time 4 rain (normal < 6 rain), activated partial thromboplastin time 26 s (normal < 32 s), prothrombin time 46 s (normal < 14.5 s) and fibrinogen 3.7 g/1 (normal 1.7-3.7 g/l). He was admitted to the hospital. Eight years before he had suffered recurrent epistaxis but this stopped after a nasal cauterization procedure. He had undergone a tooth extraction on two occasions and a tonsillectomy, all without bleeding complications. Once or twice a month he took acetylsalicylic acid for headache, without bleeding complications. He denied other medication. He smoked t5 cigarettes daily but did not drink alcoholic beverages. He had striking abnormal eating habits. He consumed neither fruit nor vegetables except for canned applesauce. However, he ate normal amounts of meat, bread and milk products and drank six cups of coffee daily. There was no family history of a hemorrhagic disorder. On examination, the patient appeared well without signs of malnutrition. The temperature was 36.7~ pulse
Clinical conferenceheld at the Leiden UniversityHospital. Members of the Department of Hematologyparticipated jointly in this conference. R. Bieger is the editor of this feature.
rate 72 beats/rain and blood pressure 160/80 mm Hg. There were hematomas in his right biceps muscle (measuring 5x18 cm), the left quadriceps muscle (6• cm) and subcutaneously on the back of the upper and lower parts of his left leg (7• and 5x15 cm). There was no mucosal bleeding. Four spider nevi were found on his chest. A grade II systolic murmur was heard over the heart. The lungs were clear. The abdomen was not distended and without signs of ascites; the liver and spleen were not enlarged. No joint abnormalities were observed. Neurologic examination was negative. The urine was normal. The hemoglobin concentration was 7.6 mmol/1, the mean corpuscular volume 90 fl, the reticulocyte count 2.7%, the platelet count 363x109/1 and the white cell count 9.8• 109/1 with normal differential counts. Urea nitrogen was 5.2 retool/I, creatinine 88 pmol/1, glucose 5.9 retool/l, total bilirubin 24 pmol/1, uric acid 0.26 retool/l, calcium 2.29 mmol/1, phosphorus 0.94 mmol/1, protein 74 g/1 (albumin 48 g/1 and globulin 26 g/l), sodium 144 retool/l, potassium 3.8 retool/l, chloride 105 retool/l, alkaline phosphatase 46 U/1 (normal 20 to 60 U/l), serum aspartate aminotransferase 9 U/1 (normal < 18 U/l), serum alanine transferase 7 U/1 (normal < 2 0 U/l) and serum lactic dehydrogenase 185 U/1 (normal < 150 U/l). The bleeding time was 165 s (normal < 240 s), prothrombin time 32 s (normal < 14.5 s), activated partial thromboplastin time 27.2 s (normal < 36.0 s), fibrinogen concentration 3.8 g/1 (normal 1.7-3.7 g/l), factor V 130~ (normal ~ 65%), factor II 111% (normal > 65%), factor VII < 1% (normal > 65%), factor X 118% (normal > 65%). The prothrombin time in a mixture of equal parts of the patient's plasma and normal plasma was 13.4 s. The patient was treated with 1 1 of fresh frozen plasma. The following morning the prothrombin time was 26 s and the factor VII concentration 4%. There was no further progression of the hemorrhages. Examination of plasma from his father and mother showed factor VII concentrations of 22% and 60%, respectively. Further laboratory tests were performed.
120
Differential diagnos& Dr. Mark Zijlmans: This 27-year-old man was admitted to the hospital with extensive muscular and subcutaneous hemorrhages without a preceding injury or other causative factor. This suggests a severe hemostatic disorder and indeed a severe clotting factor deficiency was found. The factor VII concentration was less than 1% of normal. However, until the age of 27, he had never suffered spontaneous hemorrhages. Even tooth extractions and a tonsillectomy were not complicated by abnormal bleeding. This is highly indicative of an acquired bleeding disorder. Isolated factor VII deficiency is a rare disorder with an estimated frequency of 1 per 500,000 persons. The patient's history suggests an acquired factor VII deficiency but this is extremely rare and has been described in only one case report [3]. The prolonged prothrombin time found for this patient became normal when his plasma was mixed with normal plasma which argues against a circulating anticoagulant directed against factor VII. Furthermore, the infusion of 1 1 of fresh frozen plasma significantly raised the factor VII concentration which also is not compatible with an acquired factor VII inhibitor. Congenital factor VII deficiency is transmitted as an autosomal recessive trait. For this patient the hereditary origin of the factor VII deficiency was proven by family studies. His father and mother had factor VII concentrations of 22% and 60%, respectively. Congenital factor VII deficiency is characterized by considerable genetic heterogeneity. The clinical spectrum varies from a severe hemorrhagic disorder comparable with severe hemophilia to no bleeding tendency at all [7]. Furthermore, there is not a close correlation between the factor VII concentration in a functional laboratory test and the clinical bleeding tendency. The uncomplicated tooth extractions and tonsillectomy in this patient's history would suggest that the severe factor VII deficiency has not resulted in a severe hemorrhagic disorder. Apparently, we need to find another explanation for the muscular and subcutaneous hemorrhages that occurred in this 27-year-old patient. He had a few spider nevi on his chest which could have been attributable to an acquired hepatic disease. However, the normal concentrations of the factors II, V and X exclude a disturbed hepatic clotting factor production. His diet was imbalanced, lacking in particular vegetables which are an important source of vitamin K. Significant vitamin K deficiency, however, will not develop unless the intestinal bacterial production of vitamin K is also disturbed, such as occurs after the use of antibiotics. Moreover, in this patient the vitamin K-dependent factors II and X were not deficient. Although he had taken one tablet of aspirin in this period, he did so after he experienced pain in those regions in which the hemorrhages developed two days later. Moreover, thrombocyte function, as indicated by the bleeding time, was normal at that moment and after admission to the hospital. Actually, very few acquired hemostatic disorders are likely to be present in this patient in view of the normal routine hemostatic tests, except for the factor VII defi-
ciency. The normal bleeding time excludes all quantitative and qualitative platelet disorders and is also a strong argument against acquired yon Willebrand's disease. The normal activated partial thromboplastin time excludes acquired deficiencies of factors VIII, IX and XI. The prothrombin time is markedly prolonged but this must be attributed solely to the factor VII deficiency in view of the normal factor II, V and X levels which exclude, as mentioned above, hepatic disorders and vitamin K deficiency. The normal fibrinogen level is not compatible with consumption disorders such as disseminated intravascular coagulation and primary fibrinogenolysis. The most likely remaining possibilities are acquired vascular disorders, such as purpura factitia, Cushing's syndrome, cryoglobulinemia and other types of vasculitis, amyloidosis and vitamin C deficiency. The patient exhibited no signs of corticosteroid excess. There were no palpable purpuric lesions on the lower legs as seen in cryoglobulinemia. Amyloidosis is not a likely diagnosis for a 27-year-old patient without proteinuria. Although this patient did not present with the classical syndrome of scurvy, i.e. mucosal bleeding, perifollicular hemorrhages and "corkscrew" hairs, I think the most likely diagnosis for this patient is vitamin C deficiency which can be complicated by massive subcutaneous and muscle hemorrhages [6]. His extraordinairy diet completely lacking fruit and vegetables must be insufficient for vitamin C although this also depends on the amount of potatoes he ate. It could be that the combination with the factor VII deficiency made him particularly susceptible to the hemorrhagic complications of scurvy. In conclusion I believe that this patient had a congenital factor VII deficiency and an acquired vitamin C deficiency, both contributing to the hemostatic disorder. This could be confirmed by a more extensive dietary history and measurement of the ascorbic acid level in plasma or platelets.
Clinical diagnosis Scurvy. Congenital factor VII deficiency.
Commentary Professor Ernest Briet." The subsequent dietary history revealed a vitamin C intake of 16 mg daily (recommended daily intake > 60 rag). Although he had not eaten much fruit and vegetables for as long as he could remember, his mother had been more insistent than his wife. The total lack of fruit and vegetables only applied since his marriage two years before. The vitamin C level in plasma was < 2.0/xmol/1 (reference value 15-69/~mol/1). The coincident occurrence of severe congenital factor VII deficiency and dietary vitamin C deficiency must be extremely rare and the clinician who realized that the bleeding tendency was acquired and could not be explained by the congenital factor VII deficiency deserves a compliment.
121 Congenital factor VII deficiency is a rare disorder inherited as an autosomal recessive trait. The bleeding tendency may be severe, similar to the manifestations of severe hemophilia, but surprisingly some patients with very low factor VII levels do not appear to bleed [1, 7]. A definitive explanation cannot be given but it may be that even very low levels of factor VII are sufficient for normal or near-normal hemostasis while bleeding occurs only when factor VII is completely absent. The mutations that cause factor VII deficiency may lead to decreased production of factor VII or the production of an abnormal factor VII protein [1, 4]. In the first case no factor VII antigen can be detected with immunological tests whereas in the latter normal or slightly lower levels of the antigen will be found. These abnormal or 'variant' factor VII molecules may interact differently with thromboplastins of different origin so that the deficiency can be detected only if the prothrombin time (or factor VII level) is assessed with the appropriate reagent [9]. The factor VII activity and antigen levels found for this patient and his relatives are shown in Table 1. Both parents are heterozygotes, probably with different mutations. They appear to be unrelated and exhibit differences in factor VII activity and antigen levels. The patient probably carries one gene without a product and one with some factor VII protein production. On the basis of these data it is difficult to decide which parent donated which gene. Neither the brother nor the parents exhibit signs of bleeding diathesis. Today, vitamin C deficiency is a rare cause of bleeding. The last patient with this diagnosis was seen in our hospital in 1980 [2]. Vitamin C is required for the hydroxylation reactions needed for collagen synthesis, and lack of the vitamin leads to defective collagen formation and the breakdown and degeneration of connective tissue within as well as surrounding the vessel walls. In a serious case this abnormality becomes manifest as perifollicular petechiae, ecchymoses and muscular hemorrhage, hypertrophy and bleeding of the gums, hyperkeratotic papulae of the skin and brittle, 'corkscrew' hairs. Administration of vitamin C quickly reverses the bleeding tendency as well as the other manifestations [5]. The diagnosis is based on a high index of suspicion, a careful dietary history and vitamin C plasma levels. The findings for this patient and data on a normal population as well as those with scurvy are shown in Table 2. It is clear that the paTable 1. Factor VII activity and antigen levels found for the patient
and his relatives Subject Patient Father Mother Brother
Factor VII activity* (%) < 1 22 60 43
Factor VII antigen** (%) 18 40 74 58
* Factor VII activity was measured in a one stage prothrombin time system using congenital deficient plasma as a substrate and Thromborell Dade FS as thromboplastin ** Factor VII antigen level was measured with a specific ELISA
Table 2. Vitamin C intake and plasma concentrations
Dietary vitamin C (rag daily) Patient 16 US population median* 65 Scurvy** < 10
Plasma vitamin C (~mol/1) < 2 60 < 11
* see reference 8; ** see reference 5 tient definitely had a vitamin C deficiency although his intake was not as low as in the classical case of scurvy. His dietary vitamin C was derived mainly from the three potatoes he ate daily. Because the vitamin C content in potatoes is diminished by both cooking and storage, this is not a reliable source. The history of this patient clearly shows that his factor VII deficiency alone does not give rise to bleeding. More difficult to answer is the question whether his vitamin C deficiency would have caused hemorrhages if his factor VII had been normal.
Final diagnosis Acquired bleeding tendency due to scurvy. Congenital factor VII deficiency (asymptomatic).
Addendum The patient was advised to eat vegetables, daily supplemented with rose hip jam which increased his vitamin C intake to 85 mg daily. Initially he also took vitamin C tablets, 100 mg daily. To date, there has been no recurrence of the bleeding.
References
1. Briet E, Loeliger EA, van Tilburg NH, Veltkamp JJ (1976) Molecular variant of factor VII. Thrombos Haemostas 35:289-294 2. Broekmans AW, van Brummelen P (1982) Een patiente met huid-en spierbloedingen. Ned T Geneesk 126:409-411 3. Campbell E, Sanal S, Mattson J, Walker L, Estry S, Mueller L, Schwarz M, Hampton S (1980) Factor VII inhibitor. Am J Med 68:962-964 4. Goodnight S/I, Feinstein DI, Osterud B, Rapaport SI (1971) Factor VII antibody-neutralizing material in heriditary and acquired factor VII deficiency. Blood 38:1-8 5. Hodges RE, Baker EM, Hood J, Sauberlich HE, March SC (1969) Experimental scurvy in man. Am J Clin Nutr 22:535-548 6. Hodges RE, Hood J, Canham JE, Sauberlich HE, Baker EM (1971) Clinical manifestations of ascorbic acid deficiency in man. Am J Clin Nutr 24:432-443 7. Mariani G, Mazzucconi MG (1983) Factor VII congenital deficiency. Clinical picture and classification of the variants. Haemostasis 13:169-177 8. Olsen JA, Hodges RE (1987) Recommended dietary intakes (RDI) of vitamine C in humans. Am J Clin Nutr 45:693-703 9. Triplett DA, Brandt JT, McGann Batard MA, Schaeffer Dixon JL, Fair DS (1985) Hereditary factor VII deficiency:Heterogeneity defined by combined functional and immunological analysis. Blood 66:1284-1287
Annals of
Hematology 9 Springer-Verlag 1991
Clinicopathologic Conference Acquired bleeding disorder in a patient with congenital factor VII deficiency J. M. J. M. Zijlmans, E. Briet, L . H . van Hulsteyn, J.C. Kluin-Nelemans, and R. Bieger University Hospital Leiden, Department of Hematology,Building 1: C2-R, P.O. Box 9600, 2300 RC Leiden, The Netherlands
Presentation o f case
A 27-year-old man was admitted to the hospital because of spontaneous muscular and subcutaneous hematomas. He had been well until six days before when he experienced pain in the right and left gluteal regions. Although he had played soccer the day before, he could not remember a specific trauma. He had played soccer weekly for many years without bleeding complications. For relief of pain he took one tablet of acetylsalicylic acid that same day. Four days before admission he noticed blue discolorations on his buttocks and thighs. He visited his family physician who found subcutaneous and muscular hemorrhages, prescribed ketoprofen for the pain and performed some hemostatic tests. The thrombocyte count was 220x 109/1, bleeding time 4 rain (normal < 6 rain), activated partial thromboplastin time 26 s (normal < 32 s), prothrombin time 46 s (normal < 14.5 s) and fibrinogen 3.7 g/1 (normal 1.7-3.7 g/l). He was admitted to the hospital. Eight years before he had suffered recurrent epistaxis but this stopped after a nasal cauterization procedure. He had undergone a tooth extraction on two occasions and a tonsillectomy, all without bleeding complications. Once or twice a month he took acetylsalicylic acid for headache, without bleeding complications. He denied other medication. He smoked t5 cigarettes daily but did not drink alcoholic beverages. He had striking abnormal eating habits. He consumed neither fruit nor vegetables except for canned applesauce. However, he ate normal amounts of meat, bread and milk products and drank six cups of coffee daily. There was no family history of a hemorrhagic disorder. On examination, the patient appeared well without signs of malnutrition. The temperature was 36.7~ pulse
Clinical conferenceheld at the Leiden UniversityHospital. Members of the Department of Hematologyparticipated jointly in this conference. R. Bieger is the editor of this feature.
rate 72 beats/rain and blood pressure 160/80 mm Hg. There were hematomas in his right biceps muscle (measuring 5x18 cm), the left quadriceps muscle (6• cm) and subcutaneously on the back of the upper and lower parts of his left leg (7• and 5x15 cm). There was no mucosal bleeding. Four spider nevi were found on his chest. A grade II systolic murmur was heard over the heart. The lungs were clear. The abdomen was not distended and without signs of ascites; the liver and spleen were not enlarged. No joint abnormalities were observed. Neurologic examination was negative. The urine was normal. The hemoglobin concentration was 7.6 mmol/1, the mean corpuscular volume 90 fl, the reticulocyte count 2.7%, the platelet count 363x109/1 and the white cell count 9.8• 109/1 with normal differential counts. Urea nitrogen was 5.2 retool/I, creatinine 88 pmol/1, glucose 5.9 retool/l, total bilirubin 24 pmol/1, uric acid 0.26 retool/l, calcium 2.29 mmol/1, phosphorus 0.94 mmol/1, protein 74 g/1 (albumin 48 g/1 and globulin 26 g/l), sodium 144 retool/l, potassium 3.8 retool/l, chloride 105 retool/l, alkaline phosphatase 46 U/1 (normal 20 to 60 U/l), serum aspartate aminotransferase 9 U/1 (normal < 18 U/l), serum alanine transferase 7 U/1 (normal < 2 0 U/l) and serum lactic dehydrogenase 185 U/1 (normal < 150 U/l). The bleeding time was 165 s (normal < 240 s), prothrombin time 32 s (normal < 14.5 s), activated partial thromboplastin time 27.2 s (normal < 36.0 s), fibrinogen concentration 3.8 g/1 (normal 1.7-3.7 g/l), factor V 130~ (normal ~ 65%), factor II 111% (normal > 65%), factor VII < 1% (normal > 65%), factor X 118% (normal > 65%). The prothrombin time in a mixture of equal parts of the patient's plasma and normal plasma was 13.4 s. The patient was treated with 1 1 of fresh frozen plasma. The following morning the prothrombin time was 26 s and the factor VII concentration 4%. There was no further progression of the hemorrhages. Examination of plasma from his father and mother showed factor VII concentrations of 22% and 60%, respectively. Further laboratory tests were performed.
120
Differential diagnos& Dr. Mark Zijlmans: This 27-year-old man was admitted to the hospital with extensive muscular and subcutaneous hemorrhages without a preceding injury or other causative factor. This suggests a severe hemostatic disorder and indeed a severe clotting factor deficiency was found. The factor VII concentration was less than 1% of normal. However, until the age of 27, he had never suffered spontaneous hemorrhages. Even tooth extractions and a tonsillectomy were not complicated by abnormal bleeding. This is highly indicative of an acquired bleeding disorder. Isolated factor VII deficiency is a rare disorder with an estimated frequency of 1 per 500,000 persons. The patient's history suggests an acquired factor VII deficiency but this is extremely rare and has been described in only one case report [3]. The prolonged prothrombin time found for this patient became normal when his plasma was mixed with normal plasma which argues against a circulating anticoagulant directed against factor VII. Furthermore, the infusion of 1 1 of fresh frozen plasma significantly raised the factor VII concentration which also is not compatible with an acquired factor VII inhibitor. Congenital factor VII deficiency is transmitted as an autosomal recessive trait. For this patient the hereditary origin of the factor VII deficiency was proven by family studies. His father and mother had factor VII concentrations of 22% and 60%, respectively. Congenital factor VII deficiency is characterized by considerable genetic heterogeneity. The clinical spectrum varies from a severe hemorrhagic disorder comparable with severe hemophilia to no bleeding tendency at all [7]. Furthermore, there is not a close correlation between the factor VII concentration in a functional laboratory test and the clinical bleeding tendency. The uncomplicated tooth extractions and tonsillectomy in this patient's history would suggest that the severe factor VII deficiency has not resulted in a severe hemorrhagic disorder. Apparently, we need to find another explanation for the muscular and subcutaneous hemorrhages that occurred in this 27-year-old patient. He had a few spider nevi on his chest which could have been attributable to an acquired hepatic disease. However, the normal concentrations of the factors II, V and X exclude a disturbed hepatic clotting factor production. His diet was imbalanced, lacking in particular vegetables which are an important source of vitamin K. Significant vitamin K deficiency, however, will not develop unless the intestinal bacterial production of vitamin K is also disturbed, such as occurs after the use of antibiotics. Moreover, in this patient the vitamin K-dependent factors II and X were not deficient. Although he had taken one tablet of aspirin in this period, he did so after he experienced pain in those regions in which the hemorrhages developed two days later. Moreover, thrombocyte function, as indicated by the bleeding time, was normal at that moment and after admission to the hospital. Actually, very few acquired hemostatic disorders are likely to be present in this patient in view of the normal routine hemostatic tests, except for the factor VII defi-
ciency. The normal bleeding time excludes all quantitative and qualitative platelet disorders and is also a strong argument against acquired yon Willebrand's disease. The normal activated partial thromboplastin time excludes acquired deficiencies of factors VIII, IX and XI. The prothrombin time is markedly prolonged but this must be attributed solely to the factor VII deficiency in view of the normal factor II, V and X levels which exclude, as mentioned above, hepatic disorders and vitamin K deficiency. The normal fibrinogen level is not compatible with consumption disorders such as disseminated intravascular coagulation and primary fibrinogenolysis. The most likely remaining possibilities are acquired vascular disorders, such as purpura factitia, Cushing's syndrome, cryoglobulinemia and other types of vasculitis, amyloidosis and vitamin C deficiency. The patient exhibited no signs of corticosteroid excess. There were no palpable purpuric lesions on the lower legs as seen in cryoglobulinemia. Amyloidosis is not a likely diagnosis for a 27-year-old patient without proteinuria. Although this patient did not present with the classical syndrome of scurvy, i.e. mucosal bleeding, perifollicular hemorrhages and "corkscrew" hairs, I think the most likely diagnosis for this patient is vitamin C deficiency which can be complicated by massive subcutaneous and muscle hemorrhages [6]. His extraordinairy diet completely lacking fruit and vegetables must be insufficient for vitamin C although this also depends on the amount of potatoes he ate. It could be that the combination with the factor VII deficiency made him particularly susceptible to the hemorrhagic complications of scurvy. In conclusion I believe that this patient had a congenital factor VII deficiency and an acquired vitamin C deficiency, both contributing to the hemostatic disorder. This could be confirmed by a more extensive dietary history and measurement of the ascorbic acid level in plasma or platelets.
Clinical diagnosis Scurvy. Congenital factor VII deficiency.
Commentary Professor Ernest Briet." The subsequent dietary history revealed a vitamin C intake of 16 mg daily (recommended daily intake > 60 rag). Although he had not eaten much fruit and vegetables for as long as he could remember, his mother had been more insistent than his wife. The total lack of fruit and vegetables only applied since his marriage two years before. The vitamin C level in plasma was < 2.0/xmol/1 (reference value 15-69/~mol/1). The coincident occurrence of severe congenital factor VII deficiency and dietary vitamin C deficiency must be extremely rare and the clinician who realized that the bleeding tendency was acquired and could not be explained by the congenital factor VII deficiency deserves a compliment.
121 Congenital factor VII deficiency is a rare disorder inherited as an autosomal recessive trait. The bleeding tendency may be severe, similar to the manifestations of severe hemophilia, but surprisingly some patients with very low factor VII levels do not appear to bleed [1, 7]. A definitive explanation cannot be given but it may be that even very low levels of factor VII are sufficient for normal or near-normal hemostasis while bleeding occurs only when factor VII is completely absent. The mutations that cause factor VII deficiency may lead to decreased production of factor VII or the production of an abnormal factor VII protein [1, 4]. In the first case no factor VII antigen can be detected with immunological tests whereas in the latter normal or slightly lower levels of the antigen will be found. These abnormal or 'variant' factor VII molecules may interact differently with thromboplastins of different origin so that the deficiency can be detected only if the prothrombin time (or factor VII level) is assessed with the appropriate reagent [9]. The factor VII activity and antigen levels found for this patient and his relatives are shown in Table 1. Both parents are heterozygotes, probably with different mutations. They appear to be unrelated and exhibit differences in factor VII activity and antigen levels. The patient probably carries one gene without a product and one with some factor VII protein production. On the basis of these data it is difficult to decide which parent donated which gene. Neither the brother nor the parents exhibit signs of bleeding diathesis. Today, vitamin C deficiency is a rare cause of bleeding. The last patient with this diagnosis was seen in our hospital in 1980 [2]. Vitamin C is required for the hydroxylation reactions needed for collagen synthesis, and lack of the vitamin leads to defective collagen formation and the breakdown and degeneration of connective tissue within as well as surrounding the vessel walls. In a serious case this abnormality becomes manifest as perifollicular petechiae, ecchymoses and muscular hemorrhage, hypertrophy and bleeding of the gums, hyperkeratotic papulae of the skin and brittle, 'corkscrew' hairs. Administration of vitamin C quickly reverses the bleeding tendency as well as the other manifestations [5]. The diagnosis is based on a high index of suspicion, a careful dietary history and vitamin C plasma levels. The findings for this patient and data on a normal population as well as those with scurvy are shown in Table 2. It is clear that the paTable 1. Factor VII activity and antigen levels found for the patient
and his relatives Subject Patient Father Mother Brother
Factor VII activity* (%) < 1 22 60 43
Factor VII antigen** (%) 18 40 74 58
* Factor VII activity was measured in a one stage prothrombin time system using congenital deficient plasma as a substrate and Thromborell Dade FS as thromboplastin ** Factor VII antigen level was measured with a specific ELISA
Table 2. Vitamin C intake and plasma concentrations
Dietary vitamin C (rag daily) Patient 16 US population median* 65 Scurvy** < 10
Plasma vitamin C (~mol/1) < 2 60 < 11
* see reference 8; ** see reference 5 tient definitely had a vitamin C deficiency although his intake was not as low as in the classical case of scurvy. His dietary vitamin C was derived mainly from the three potatoes he ate daily. Because the vitamin C content in potatoes is diminished by both cooking and storage, this is not a reliable source. The history of this patient clearly shows that his factor VII deficiency alone does not give rise to bleeding. More difficult to answer is the question whether his vitamin C deficiency would have caused hemorrhages if his factor VII had been normal.
Final diagnosis Acquired bleeding tendency due to scurvy. Congenital factor VII deficiency (asymptomatic).
Addendum The patient was advised to eat vegetables, daily supplemented with rose hip jam which increased his vitamin C intake to 85 mg daily. Initially he also took vitamin C tablets, 100 mg daily. To date, there has been no recurrence of the bleeding.
References
1. Briet E, Loeliger EA, van Tilburg NH, Veltkamp JJ (1976) Molecular variant of factor VII. Thrombos Haemostas 35:289-294 2. Broekmans AW, van Brummelen P (1982) Een patiente met huid-en spierbloedingen. Ned T Geneesk 126:409-411 3. Campbell E, Sanal S, Mattson J, Walker L, Estry S, Mueller L, Schwarz M, Hampton S (1980) Factor VII inhibitor. Am J Med 68:962-964 4. Goodnight S/I, Feinstein DI, Osterud B, Rapaport SI (1971) Factor VII antibody-neutralizing material in heriditary and acquired factor VII deficiency. Blood 38:1-8 5. Hodges RE, Baker EM, Hood J, Sauberlich HE, March SC (1969) Experimental scurvy in man. Am J Clin Nutr 22:535-548 6. Hodges RE, Hood J, Canham JE, Sauberlich HE, Baker EM (1971) Clinical manifestations of ascorbic acid deficiency in man. Am J Clin Nutr 24:432-443 7. Mariani G, Mazzucconi MG (1983) Factor VII congenital deficiency. Clinical picture and classification of the variants. Haemostasis 13:169-177 8. Olsen JA, Hodges RE (1987) Recommended dietary intakes (RDI) of vitamine C in humans. Am J Clin Nutr 45:693-703 9. Triplett DA, Brandt JT, McGann Batard MA, Schaeffer Dixon JL, Fair DS (1985) Hereditary factor VII deficiency:Heterogeneity defined by combined functional and immunological analysis. Blood 66:1284-1287
