Background

Dysfibrinogenaemia is a rare disorder of haemostasis and has important implications for the management of a pregnant patient and the fetus. There are a few reported cases and reviews that address the management of pregnancy in a patient with dysfibrinogenaemia and there are no current therapeutic guidelines.1 2 In this case, we successfully managed a patient whose pregnancy was complicated by vaginal bleeding due to congenital dysfibrinogenaemia. Given the autosomal dominant nature of dysfibrinogenaemia, we emphasise the importance of an interdisciplinary approach between physicians from the departments of obstetrics-gynaecology, haematology and paediatric haematology. Finally, we highlight the importance of using family history along with laboratory data in ruling out acquired forms of fibrinogen disorder.

Case presentation

The patient is a 26-year-old woman G1P0 at 31 weeks gestation with a medical history of asthma, fibromyalgia and Raynaud’s disease who presented with clear vaginal discharge and mild intermittent vaginal bleeding. The patient reported positive fetal movement and irregular uterine contractions. She was initially evaluated at a referring local hospital with findings of ruptured membranes, with subsequent administration of betamethasone, and transported to our hospital for possible concern of placental abruption. On arrival, a bedside ultrasound showed vertex presentation with anterior placenta and decreased amniotic fluid with an amniotic fluid index of 4.18 cm. There were no signs of preterm labour, placental abruption or infection, and she was admitted for further evaluation of preterm premature rupture of the membranes and vaginal bleeding. Initial laboratory tests showed a critical low value for fibrinogen at 76 mg/dL, with high normal prothrombin time (PT) and normal partial thromboplastin time(PTT).

Investigations

Initial laboratory investigation was notable for white cell count of 11.0×10⁹/L (reference: 4.1–9.3×10⁹/L), haemoglobin of 100.0 g/L (reference: 110.0–147 g/L) and platelets of 240×10⁹/L (reference: 130–350×10⁹/L). Liver function tests showed total bilirubin of 0.4 mg/dL (reference: 0.1–1.2 mg/dL), alkaline phosphatase of 102 IU/mL (reference: 30–115 IU/mL), aspartate transaminase of 17 IU/mL (reference: 5–45 IU/mL) and alanine transaminase of 12 IU/mL (reference: 5–60 IU/mL). Total protein was 6.5 g/dL (reference: 6.0–8.0 g/dL), albumin was 3.2 g/dL (reference: 3.5–5.2 g/dL), calcium was 8.6 mg/dL (reference: 8.6–10.3 mg/dL), creatinine was 0.58 mg/dL (reference: 0.6–1.20 mg/dL) and urea nitrogen was 7 mg/dL (reference: 7–22 mg/dL), with an estimated glomerular filtration rate >60 mL/min/1.73 m². Coagulation studies are outlined in table 1.

A more extensive autoimmune evaluation was performed which found a slightly elevated antinuclear antibody of 160 (reference: <160 titre) and normal rheumatoid factor, anticardiolipin IgG, anticardiolipin IgM, anticardiolipin IgA, beta-2 glycoprotein G, beta-2 glycoprotein M, beta-2 glycoprotein IgA, double-stranded DNA antibodies, ribonucleoprotein antibodies and Smith antibodies.

Differential diagnosis

In the evaluation of low fibrinogen levels in a pregnant patient, it is important to first consider acquired causes as these defects are more common than any inherited defects. Acute disseminated intravascular coagulation (DIC) is the most common cause of acquired hypofibrinogenaemia and the diagnosis to consider first in a patient at 31 weeks gestation presenting with premature rupture of the membranes, mild vaginal bleeding and concern for placental abruption. DIC is a coagulopathy that often causes thrombocytopaenia, prolonged PT and activated partial thromboplastin time (aPTT), low plasma fibrinogen, elevated D-dimer, signs of mucosal bleeding, arterial/venous thrombosis, and organ dysfunction especially renal failure, hepatic dysfunction and acute lung injury. The suspicion for DIC was low given the relatively small amount of bleeding and lack of signs of organ failure. Furthermore, the PT and aPTT were within normal limits and there was no thrombocytopaenia. The next most common cause of acquired low fibrinogen is liver failure, and this patient had no signs of liver abnormalities as Liver function tests were within normal limits, there was no coagulopathy and total bilirubin was within normal limits. Within the area of acquired hypofibrinogenaemia, there are several disorders that produce autoantibodies that target fibrinogen, including systemic lupus erythematosus, rheumatoid arthritis and antiphospholipid antibody syndrome, but all of these titres came back negative. Finally, a consideration was given for multiple myeloma as a cause but there was very low suspicion to complete a full work-up as the patient denied any bone pain and weight loss and laboratory results showed no hypercalcaemia, normal total protein levels and no elevation in creatine. Finally, she only had anaemia that could be attributed to her pregnancy. Other more frequent acquired causes of hypofibrinogenaemia are secondary to asparaginase, valproic acid or tissue Plasminogen Activator (tPA), which our patient has not received any prior to presentation.

Without a likely acquired cause of low fibrinogen levels, we turned our attention to congenital aetiologies. Congenital disorders of fibrinogen are divided into quantitative (afibrinogenaemia, hypofibrinogenaemia) and qualitative (dysfibrinogenaemia, hypodysfibrinogenaemia). Dysfibrinogenaemia and hypofibrinogenaemia have a wide range of clinical manifestations, from minor to life-threatening bleeding or thrombosis.3–6 When considering the differences between dysfibrinogenaemia and hypofibrinogenaemia, a family history is crucial because dysfibrinogenaemia is an autosomal dominant disorder, whereas hypofibrinogenaemia is more commonly an autosomal recessive disorder but can be either.2 7 In family history, the patient mentioned that her mother was recently told that she had low fibrinogen during a work-up for an elective orthopaedic procedure, but the procedure was completed with no issues according to the patient. Another important note in the history was the patient’s observation of increased bruising during pregnancy compared with her baseline. In the laboratory work-up, hypofibrinogenaemia commonly has a decreased level of fibrinogen, with both activity and fibrinogen antigen between 50 mg/dL and the lower limit of normal range for local laboratory.3 The patient’s PT and aPTT were both within normal limits. She did have a low fibrinogen activity level at 76 mg/dL at admission and an increased fibrinogen antigen at 696 mg/dL. At this point the diagnosis of dysfibrinogenaemia was strongly favoured due to elevated fibrinogen antigen level and low activity level. It is essential to consider the elevated fibrinogen antigen at 696 mg/dL, increased thrombin time at 27.6 s and the increased reptilase time of 29.7 s. Dysfibrinogenaemia is characterised by classically low functional levels of fibrinogen compared with normal or increased immunological assays of fibrinogen antigen.3 An increased reptilase time is another laboratory value that provides strong evidence of dysfibrinogenaemia.3 In conclusion, it was the patient’s history of increased bruising during pregnancy, her positive family history including data from her mother, and the patient’s laboratory data that gave the team confidence in the diagnosis of congenital dysfibrinogenaemia.

Treatment

Although the patient’s vaginal bleeding had stopped before treatment, it is known that major bleeds can occur during delivery from mechanical trauma. Also there is a known increase in the prevalence of placental abruption in women with low fibrinogen levels who did not receive any fibrinogen replacement, especially if the level falls below 50 mg/dL.3 8 9

Literature review for the treatment of dysfibrinogenaemia during pregnancy suggests goal of maintaining functional fibrinogen levels between 50 mg/dL and 100 mg/dL.3 10

There are different available sources of fibrinogen, such as cryoprecipitate, fresh frozen plasma and lyophilised fibrinogen. Fibrinogen product is the best option; however, it was not readily available at our institution and we tried not to give fresh frozen plasma to avoid hypervolaemia. The patient received 10 units of cryoprecipitate 10 days before delivery when her fibrinogen level was 76 mg/dL after collecting the initial diagnostic specimen, and then she remained under observation by the multidisciplinary team until her delivery. The labour was induced at 33 weeks and 4 days. She received additional 10 units of cryoprecipitate immediately post partum. Extra units of cryoprecipitate in addition to tranexamic acid were available all the time for this patient in the event she needed if clinically warranted. Just before delivery, her fibrinogen level was 44 mg/dL. The plan was also to give continuous cryoprecipitate infusion if the patient had shown any signs of DIC or significant haemorrhage. Given the patient’s mother’s history of fibrinogen disorder, it was presumed that the newborn has fibrinogen disorder as well. For this reason, we recommended against the usage of vacuum or forceps during delivery and a low threshold for caesarean section. If the patient needed a caesarean section, she should have received a continuous infusion of cryoprecipitate as recommended in the literature.2 Finally, a paediatric haematologist was consulted with strong likelihood of the child having dysfibrinogenaemia and the risk involved with umbilical cord haemorrhage and bleeding from potential circumcision.

Outcome and follow-up

The patient had uneventful vaginal delivery with no epidural procedure. The day following discharge she was given one dose of low molecular weight heparin 40 mg as there is increased concern for postpartum thrombosis.11 The patient did not have any bleeding or thrombotic events post partum and she was discharged 2 days later with no anticoagulation with plans for outpatient follow-up with the haematologist. Her son was seen in the neonatal intensive care unit by the paediatric haematologist, where he was found to have a low fibrinogen level less than 35 mg/dL and a normal fibrinogen antigen level of 283 mg/dL (reference: 180–305 mg/dL), and he was subsequently diagnosed with congenital dysfibrinogenaemia (figure 1). The paediatric haematology team recommended that the patient defer circumcision until appropriately dosed cryoprecipitate products could be acquired by the pharmacy and special arrangements could be made with paediatric urologists. Four months post partum the mother followed up with the haematologist, where she reported that her ease of bruising had resolved and she denied any new health problems. Her laboratory findings at this outpatient encounter revealed a fibrinogen level less than 35 mg/dL, but since she was without any signs of bleeding or thrombosis it was determined that she did not need any acute intervention. The patient was informed that she will need cryoprecipitate before any invasive medical procedures and was advised to follow up with the haematologist if she were to become pregnant in the future.

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Figure 1

The patient’s pedigree with family history of dysfibrinogenaemia. (A) The patient’s mother with fibrinogen level <35 mg/dL. (B) The 26-year-old patient with fibrinogen level of 76 mg/dL and fibrinogen antigen of 650 mg/dL. (C) The patient’s newborn son with fibrinogen level <35 mg/dL and fibrinogen antigen of 283 mg/dL.