Learning Objectives• Recognize when diagnosis momentum may be hindering

identification of the true condition.• Differentiate causes of combined PT and PTT prolongation.• Summarize the features of congenital afibrinogenemia.• Identify treatment options for afibrinogenemia.

Discovery of Congenital Afibrinogenemia Delayed By Diagnosis Momentum

A. Min Kang, MD, PGY4; Young-Na Lee-Kim, MD1

1Baylor College of Medicine, Department of Pediatrics, Section of Hematology-Oncology

ResultsAST: 43 U/L Albumin: 3.3 g/dLALT: 32 U/L Unconj Bili: 0.1 mg/dLGGT: 15 U/L Conj Bili: 0 mg/dL

White Blood Count: 6.2 x 103/μL Hemoglobin: 10.3 g/dLPlatelet Count: 260 x 103/μL Hematocrit: 31.4%

Peripheral Smear: No schistocytesAbstract

Case ReportA 21-month old female with no previous medical history presented to the Emergency Department (ED) with an 11-day history of left cheek swelling. The patient’s mother first noticed the swelling when she picked the patient up from daycare but no history of trauma was noted by the staff. That evening, the patient went to an urgent care facility where facial radiographs were negative for fracture and she was sent home with a prescription for amoxicillin. Three days later, due to persistent swelling, progressive dark skin discoloration, drooling, and trouble chewing, the patient saw her pediatrician, where a mandible radiograph was again negative for fracture (though soft tissue swelling was noted). Her prescription was changed to amoxicillin/clavulinic acid and she was sent home. At her pediatrician follow-up one week later, discoloration had mostly resolved but a soft mass remained over the left mandible. Her antibiotics were changed to clindamycin and she was sent home with a referral to otolaryngology.

Later that evening, the patient’s mother brought the patient to the ED because she felt more evaluation was needed. Ultrasonography of the face showed a left-sided fluid collection concerning for abscess so the patient was admitted for intravenous antibiotics. The following morning, computed tomography (CT) of the face confirmed an isolated fluid collection and she was taken to the Operating Room (OR) by the otolaryngologist who drained a bloody fluid collection from the cheek.

In view of the frankly bloody aspirate and a radiologist’s concern of cortical irregularities in other facial bones on the CT, evaluation for a bleeding disorder was initiated. Upon further questioning, the mother reported that the child had significant bleeding from the umbilical stump as a neonate, which prompted an ED visit at that time; however, she was reassured that this was normal and was discharged home. Moreover, easy bruising from daily activities had also been discussed with her pediatrician and the family was again given reassurance that this was normal. This new history coupled with lab testing quickly led to the diagnosis.

DiscussionOur patient’s cheek swelling and discoloration was assumed to be infectious in nature and treated with antibiotics. Each subsequent healthcare interaction, including the initial inpatient treatment, continued on the same course despite a lack of local or systemic signs of infection and a persistent fluid collection despite treatment. This diagnostic momentum, in which a previous diagnosis is accepted without question, led to a delay in discovering the actual condition as well as an OR procedure that could have had adverse consequences. This case demonstrates the importance of remaining open to alternatives when the details of the case do not fit. In retrospect, our patient displayed symptoms of a bleeding disorder beginning in infancy.

Congenital fibrinogen deficiency is one of the rarest bleeding disorders and can be qualitative (dysfibrinogenemia) or quantitative (hypofibrinogenemia or afibrinogenemia). The subtype can be distinguished by combining functional and antigen assays for fibrinogen. Low activity and normal antigen supports dysfibrinogenemia while low levels of both activity and antigen indicates hypofibrinogenemia. Undetectable fibrinogen activity and antigen is diagnostic for afibrinogenemia, which has a prevalence of only 1 in 1,000,000 worldwide and tends to have the most frequent and severe bleeding episodes.

Due to umbilical stump bleeding (as was noted in our patient), afibrinogenemia is often diagnosed early in life. Serious bleeding can also occur in the central nervous system, gastrointestinal tract, joints, or muscle. The latter can be a complication of childhood immunizations (which was also subsequently noted in our patient). Later in life, females often have menorrhagia and problems with fertility and pregnancy.

Treatment can be with anti-fibrinolytic agents such as aminocaproic acid, or with transfusions of fresh frozen plasma, cryoprecipitate, or fibrinogen concentrate—the preferred replacement. Aminocaproic acid was given to this patient during a subsequent ED visit for epistaxis, after which she developed painful arm swelling within one day and was found to have a cephalic vein thrombosis. This corresponds to the increased thrombosis risk that can exist due to dysregulation of mutated fibrinogen. If treatment is needed, strategies should target prophylaxis, major bleeds, pre-surgery, and pregnancy.

References1. Acharya & Dimichele (2008). Rare inherited disorders of

fibrinogen. Haemophilia. 14: 1151-8.2. Bornikova et al (2011). Fibrinogen replacement therapy for

congenital fibrinogen deficiency. J Thromb Haemost. 9: 1687-704.3. Peyvandi (2012). Epidemiology and treatment of congenital

fibrinogen deficiency. Thromb Res. 130 Suppl 2: S7-11.

Texas Pediatric Society Electronic Poster Contest

Figure 1. Ultrasound of left cheek showed a 4.2 x 3.5 x 2.4 cm fluid collection with some increased internal echogenicity surrounding the body of the left mandible. There was no cortical defect in the body of the mandible. The parotid and submandibular glands were normal in appearance.

Lab Test Before Cryo

After Cryo

Prothrombin Time (PT) (s) > 100 17International Normalized Ratio (INR)

> 12.4 1.4

Partial Thromboplastin Time (PTT) (s)

> 150 39.7

PTT Hepzyme (s) > 150 36.4Thrombin Time [15 – 19 s] > 120 27.4Reptilase Time [16.3 – 19.8 s] > 100D-dimer (mcg/mL) 0.27 < 0.22Fibrinogen Activity [220 – 440 mg/dL]

< 15 62

Fibrinogen Antigen [149 – 353 mg/dL]

< 45

Figure 2. CT with contrast showed a 4.3 x 3.5 x 2.9 cm subperiosteal homogenous non-enhancing low-density fluid collection surrounding the left mandible.

Congenital fibrinogen deficiency is a rare bleeding disorder due to decreased fibrinogen activity or level. Bleeding is variable in dysfibrinogenemia but common early in life in afibrinogenemia due to complete absence of fibrinogen. Fibrinogen replacement therapy is available but may be complicated by thrombosis tendency due to dysregulation of mutated fibrinogen. Here, we describe a case of congenital afibrinogenemia diagnosed only after persistent treatment for cellulitis and abscess did not resolve the patient’s symptoms.

Initial coagulation studies noted a PT/INR and a PTT that did not clot, leading to the following differential diagnosis:•Liver disease•Disseminated Intravascular Coagulation (DIC)•Medications: - Supratherapeutic heparin or warfarin

- Direct Thrombin Inhibitor•Deficiency/Inhibitor of Factor V or X, prothrombin, or fibrinogen

Normal physical exam of the abdomen and liver function studies argued against liver disease. Normal bilirubin, D-dimer, platelet count, and peripheral smear review made DIC unlikely. The patient had no known access to heparin, warfarin, or direct thrombin inhibitors. This was supported by the prolonged reptilase time and hepzymed PTT, which also indicated an underlying coagulation defect. Ultimately, the history of significant umbilical stump bleeding and an undetectable fibrinogen was consistent with a congenital deficiency. The patient was treated empirically with cryoprecipitate both to confirm the clinical suspicion and to minimize re-bleeding into the left cheek that had been drained earlier that day. All lab values corrected (see table above) following the transfusion and the fibrinogen antigen was eventually found to be undetectable, confirming the diagnosis of afibrinogenemia.

Clinical Pearls• Be aware of diagnosis momentum as a potential source of error in

the setting of a prolonged atypical clinical course.• Although combined PT and PTT prolongation is commonly due

to liver disease, DIC, or direct thrombin inhibitors, congenital bleeding disorders should also be in the differential.

• Congenital afibrinogenemia is rare and often presents with significant umbilical stump bleeding, but can also carry an increased risk of thrombosis.

• Fibrinogen concentrate is the preferred replacement therapy, however, cryoprecipitate can be used if fibrinogen concentrate is not readily available.