Congenital disorders of fibrinogen.
Inherited disorders of fibrinogen, especially those associated with a significant bleeding tendency, are rare. As against this, acquired abnormalities are extremely common, e.g., dysfibrinogenemia in liver diseases and hypofibrinogenemia in consumptive coagulopathy.
We are reporting 5 cases of congenital disorders of fibrinogen from 3 unrelated families seen by us during the last year. Nine cases of congenital quantitative deficiency of fibrinogen have been reported in the Indian literature so far., , , , ,  No case of congenital dysfibrinogenemia is reported in the Indian literature., 
All the coagulation studies were carried out by using standard methods. Clottable fibrinogen was quantitated by using the modified method of Ratnoff and Menzie, and Shaw and by the method of Clauss (as quoted by Beck). Heat denaturation and chemical precipitation by using either saturated ammonium sulfate or sodium sulfite were the methods used for detection and quantitation of precipitable fibrinogen.
M.B., a 4 day old male child from a Sunni Muslim family was brought for bleeding from the umbilical stump for 24 hours. He was a full Term normal delivery from a consanguinous marriage. He had two siblings, both being asymptomatic. There was no history of excessive bleeding in any other family member. During the hospital stay, the child developed hematoma at the blood collection site. He was also noticed to have occasional ecchymotic spots on the back. Besides this, his examination was unremarkable with no evidence of liver disorder or consumptive coagulopathy. Coagulation studies showed complete absence of fibrinogen (Table 1). The studies carried out 2 months later, showed the same results. The liver function tests and renal chemistry were normal. Similar studies carried out in both the siblings and parents were entirely normal (Table 2). The child received 30 ml of plasma which resulted in complete stoppage of bleeding. No complications were noticed.
Y.G., a 4 year old male child from a non-consanguinous marriage was noticed to have prolonged bleeding from the puncture sites after intramuscular injections. The bleeding used to last for 15-40 minutes. There was no history of bleeding at the time of separation of umbilical cord. He had 3 brothers, one of whom had died at the age of 6 years due to an unrelated illness while one had undergone circumcision without excessive bleeding. Other family members had no history suggestive of excessive bleeding. The child was normal on clinical examination. The coagulation studies carried out showed quantitative deficiency of fibrinogen (Table 1). Repeat studies carried out two months later confirmed the findings. The liver function tests and the renal chemistry were normal. The coagulation studies including the fibrinogen level carried out in both the siblings and parents were normal (Table 2).
A.B., a 2 year old male child from a consanguinous marriage was brought for prolonged bleeding from a scalp wound following a trauma. The bleeding had continued for 36 hours and had necessitated blood transfusion. There was a history of prolonged bleeding for 24 hours after the separation of the umbilical cord. He also had occasional episodes of epistaxis and easy bruising. He had three sisters and one brother of whom one was a bleeder (Case 4). One sister had died following prolonged umbilical cord bleeding on the seventh day of life. In addition, his cousin brother (Case 5) was a bleeder. Parents had no history suggestive of prolonged bleeding. Clinical examination was normal except for the scalp wound. The coagulation studies revealed dysfibrinogenemia (Table 1). The liver function tests and renal chemistry were normal. Investigations in parents and remaining 2 siblings gave normal results (Table 2). Bleeding responded to plasma therapy.
P.B., a 51 year old female patient, sister of the Case 3, was a full term normal delivery but had a severe episode of bleeding from the site of the umbilical stump on the fifth day of birth. This necessitated blood transfusion. Since then, the patient has remained alright except for easy bruising and prolonged bleeding from cuts. Clinical examination was normal while coagulation studies confirmed dysfibrinogenemia (Table 1). Family details are as described in Case 3 (Table 2).
I.I., a 4 year old male child, cousin brother of Cases 3 and 4 was seen for an episode of massive intramuscular hematoma in the left thigh following a fall. He also had a severe bleeding after fall of the umbilical cord at the age of 7 days when transfusion was needed. He was a full term normal delivery from a consanguinous marriage. Clinical examination revealed a massive intramuscular hematoma in the left thigh with bluish discolouration of the skin. Investigations confirmed dysfibrinogenemia (Table 1). His parents were normal, both clinically and on investigations (Table 2) while he had no siblings. He responded to plasma therapy which was given in doses of 30 ml/kg as a loading dose and 10 ml/kg twice a week as a maintenance dose for the next 15 days.
Congenital afibrinogenemia was first described in 1920. Hypofibrinogenemia, a less clearly defined disorder, was first described in 1935. The first well documented case of congenital dysfibrinogenemia was described in 1964. Almost 40 cases of abnormal fibrinogen have been described till now. Afibrinogenemia appears to be an autosomal recessive disorder and consanguinity is present in over 50 per cent of the families. The disorder is equally common in both males and females and parents have normal or slightly decreased fibrinogen concentration. The affected individual is homozygous for the deficiency. Hypofibrinogenemia may represent a heterozygous state of afibrinogenemia but no definite pattern of inheritance has been worked out.,  Congenital days fibrinogenemia appears to be due to a qualitative defect in the fibrinogen molecule. Majority of them are inherited in an autosomal dominant fashion. They exhibit defective fibrin monomer aggregation. Hypofibrinogenemia and dysfibrinogenemia have been encountered in the same family. Because of the affection of a single member, it was difficult to comment upon the nature of inheritance in the first two cases described above. However, Cases 3-5 are likely to be inherited in an autosomal recessive fashion. Only twice before, a case of congenital dysfibrinogenemia has been shown to have an autosomal recessive inheritance.
Clinically, patients of afibrinogenemia have a variable severity. Bleeding after falling of umbilical cord is a characteristic finding of afibrinogenemia as of Factor XIII deficiency. Besides this, bleeding is invariably noted in the first few days of life particularly from gastro-intestinal tract, genitourinary tract and in central nervous system. Similarly, easy bruising and gingival hemorrhages are common. Rarely hemarthrosis could occur Thus the pattern of bleeding is quite different from that in classical hemophilia. As against this, most of the patients with hypofibrinogenemia have no hemorrhagic manifestations. Occasional patient may have mild bleeding tendency in the form of easy bruising. However, fatal postoperative bleeding is known. Most of the cases are detected as a pre-operative work up or when they present for prolonged and excessive post-operative bleeding. Symptomatology of dysfibrinogenemia is variable. Patients could present for excessive bleeding, thrombosis or wound dehiscence. Recently, asymptomatic cases are reported following increasing use of coagulation tests.
In afibrinogenemia whole blood clotting time, prothrombin time, partial thromboplastin time, thrombin time are all prolonged and they are correctable by the addition of normal plasma or normal fibrinogen to the patient's plasma. There is no detectable plasma fibrinogen by almost all physicochemical methods i.e. precipitation using heat (56°C for 10 minutes), ammonium sulfate or sodium sulphite, or on functional assay e.g. thrombin clotting time. All these tests carried out in Case 1 had shown total lack of fibrinogen. It has been said, that by using sensitive immunological techniques, a trace amount of plasma fibrinogen (upto 5.0 mg%) can be detected. In hypofibrinogenemia, results of coagulation tests vary with the amount of fibrinogen present. Majority of patients have a plasma fibrinogen level in the range of 20 to 100 mg/dl22. In the case described here, precipitation with ammonium sulfate or sodium sulphite and measurement of clottable fibrinogen by diluting plasma gave a subnormal but similar results (Table 1). Although abnormal fibrinogen may be present, the results favoured a diagnosis of hypofibrinogenemia. Lastly, the discrepancy in the amount of precipitable fibrinogen (physiochemical methods) and clottable fibrinogen in Cases 3-5 suggested dysfibrinogenemia with or without quantitative deficiency., 
Platelet disorders in these conditions deserve a separate discussion. Onefourth of the cases of fibrinogen deficiency have a prolonged bleeding time, thrombocytopenia and/or a defective platelet aggregation. These are all partially or totally correctable by addition of fibrinogen,  or even heparin. No platelet aggregation studies were carried out in the cases described here but the platelet count, aggregates in the peripheral smear and bleeding time were normal. Many authors have demonstrated a low fibrinogen content of the afibrinogenemic platelets. Fatal thromboembolic complications are also known in these disorders. They were thought to result from the therapy but cases unrelated to treatment are also described. This is an unexplainable complication of this disorder and must be kept in mind especially during the treatment of a bleeding episode.
Regarding treatment, no prophylaxis should be attempted. Fibrinogen levels of 50-100 mg% are adequate to maintain normal haemostasis. As discussed, many patients have high susceptibility to thrombosis, if treated with purified fibrinogen. Similarly, the incidence of hepatitis B is very high with purified fibrinogen from donor pools. Clinical use of fresh plasma or cryoprecipitate will give adequate hemostasis except in rare conditions. The plasma transfusion in the first case was adequate to stop umbilical cord bleeding while the case with hypofibrinogenemia never needed replacement therapy. All the bleeding episodes in Cases 3, 4 and 5 could be easily controlled with plasma therapy.
We are thankful to Dr. C. K. Deshpande, Dean, Seth G. S. Medical College and K.E.M. Hospital for allowing us to publish the work done in this hospital.