Spontaneous haemopericardium due to vitamin K deficiency in an adult patient with cardiofaciocutaneous syndrome

Abstract

We present the case of an adult man with cardiofaciocutaneous syndrome, who initially presented to the emergency department with severe abdominal pain and distension, but was diagnosed with cardiac tamponade on CT after distended neck veins and tachycardia were identified on examination. He had emergency pericardial drainage to relieve the haemopericardium and was treated with colchicine. He was further found to be deficient in factors II, VII and X despite not being on warfarin, and was therefore supplemented with vitamin K. This confirms a diagnosis of vitamin K deficiency, likely multifactorial from malabsorption due to chronic intestinal pseudo-obstruction, small bowel obstruction and possibly exacerbated by subsequent ciprofloxacin use for small intestine bacterial overgrowth. This is the first report of spontaneous haemopericardium secondary to vitamin K deficiency in an adult patient not on anticoagulation, and is an important learning point due to the life-threatening progression of the haemopericardium and cardiac tamponade.

Background

Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder caused by a mutation in one of the genes involved in Ras/mitogen-activated protein kinase signalling. More than 100 cases of CFC have been reported in the literature, but it is estimated there are several hundred people worldwide affected.¹ The condition is characterised by brittle hair; macrocephaly; bitemporal narrowing; learning difficulty; failure to thrive; cardiac defects; short stature and skin abnormalities. There is phenotypic overlap with Noonan and Costello syndrome. Congenital heart defects are present in over 75% of patients, commonly pulmonary stenosis and atrial or ventricular septal defects. Many children first present with failure to thrive and gastrointestinal problems manifest as gastro-oesophageal reflux, aspiration, vomiting, eating avoidance, intestinal malrotation, dysmotility and constipation. Diagnosis is based on clinical findings and molecular genetic testing. The four genes known to be associated with CFC are BRAF (~75%), MAP2K1 and MAP2K2 (~25%), and KRAS (<2%).¹

Haemopericardium describes the collection of blood within the pericardial sac. This can lead to cardiac tamponade, characterised by impairment of diastolic ventricular filling resulting in reduced cardiac output which, if not managed promptly, can result in cardiac arrest.² Haemopericardium can be iatrogenic (eg, due to anticoagulation therapy or pericardial injury), occur due to malignancy, atherosclerosis, congenital clotting disorders or even be idiopathic.³ Clinical presentation is often described as a triad of distended neck veins, hypotension and muffled heart sounds (Beck’s triad), although depending on symptom timing and the exact cause the presentation of tamponade can vary greatly. Therefore, it is vital to identify the cause and treat accordingly to prevent tamponade.

We report on a patient with a background of CFC who developed haemopericardium and cardiac tamponade secondary to vitamin K deficiency. This is the first case of spontaneous haemopericardium secondary to vitamin K deficiency described in an adult not on anticoagulation therapy.

Case presentation

A patient in his 20s with known CFC (secondary to c.389A>G (p.Tyr130Cys) mutation in the MAP2K1 gene) attended the emergency department with severe non-radiating epigastric and periumbilical abdominal pain and abdominal distension. He had vomited in the ambulance and opened his bowels earlier in the day, producing a large volume of loose stool without solid pieces (type 7 on the Bristol Stool Chart). He also had a temperature of 37.9°C on arrival.

Due to the learning difficulty in patients with CFC, there was a difficulty in clarifying exact symptoms, particularly regarding determining a specific area of pain. The patient’s medical history includes a balloon valvotomy shortly after birth for pulmonary valve stenosis, and he is being followed up in a specialist cardiothoracic centre. He had been admitted a few months earlier with an episode of chronic constipation and intestinal pseudo-obstruction, showing symptomatic improvement after a course of long-term laxatives. He exhibited cutaneous features of CFC such as dry skin, hyperkeratosis pilaris and multiple naevi (figure 1), as well as facial features including sparse eyebrows with underlying skin reddening, a hypoplastic nasal bridge, low set posteriorly rotated ears and sparse curly hair.

Figure 1.

Picture of a rash on the patient’s back, illustrating dry skin, hyperkeratosis pilaris and multiple naevi.

On examination, the patient had a heart rate of 120–135 beats/minute and a systolic blood pressure of 90–120 mm Hg, as well as neck vein distension. His SpO₂ gradually deteriorated, starting at 90% on air then dropping to 85% on 15 L O₂. He was peripherally cool but had a strong radial pulse and no signs of heart failure. His abdomen was distended and hypertympanic with tinkling bowel sounds, tender to palpation with guarding over the left upper quadrant and periumbilical area.

Due to his abdominal distension and haemodynamic compromise, he was planned to undergo a CT of the abdomen and pelvis. However, considering his history of congenital heart disease and also as the clinical features indicated suspicion of tamponade, a thoracic CT was also included in the request, leading to the identification of a large haemopericardium. This was followed by an echocardiogram to assess the haemopericardium, leading to the decision to arrange transfer for pericardiocentesis and drain insertion

Investigations

Blood results showed deranged clotting factors with a raised PT and INR. Factor assays showed a deficiency in factor II, V, VII and X, which highlighted the diagnosis of vitamin K deficiency (table 1).

Table 1.

Table of the patient’s blood results on admission

Clotting panel	Reference range	Result
APTT (Activated partial thromboplastin time)	26.0–32.7 s	28.9
D-dimer	0–230 ng/mL	779 (elevated)
FGN	1.46–3.33 g/L	4.34 (elevated)
INR (International normalised ratio)	1.00–1.15 INR	1.61 (elevated)
PT (Prothrombin time)	10.3–12.9 s	19.9 (elevated)
Factor II assay	0.53–1.38 IU/mL	0.45 (low)
Factor V assay	0.67–1.28 IU/mL	0.39 (low)
Factor VII assay	0.62–1.27 IU/mL	0.23 (low)
Factor IX assay	0.75–1.55 IU/mL	1.08
Factor X assay	0.64–1.44 IU/mL	0.61 (low)
Factor XII assay	0.53–1.71 U/mL	0.69
Factor XIII antigen	0.50–1.40 U/mL	0.52
vWF antigen	0.53–1.49 IU/mL	2.27 (elevated)
vWF Ristocetin cofactor	0.52–1.34 IU/mL	2.13 (elevated)

There is a clear derangement of his clotting factors, with a very elevated PT and INR, indicating specifically a derangement of the extrinsic coagulation pathway. In addition, factors II, V and VII are all deranged, leading to the diagnosis of vitamin K deficiency.

CT imaging of the chest, abdomen and pelvis found a new large haemopericardium and a grossly dilated sigmoid colon without a volvulus, bowel obstruction or perforation (figure 2). The left superficial femoral vein had a filling defect, which raised suspicion of a thrombus. Indeterminate splenic lesions were identified but characterisation was not possible from CT findings.

Figure 2.

CT cross-section of the patient’s chest (anonymised), very clearly illustrating a large volume haemopericardium of >2 cm in diameter.

A transthoracic echocardiogram was performed, which showed a large circumferential pericardial effusion (~3.6 cm at its largest adjacent to right atrium in PSAX view, 2.7 cm anterior to the RVOT (right ventricular outflow tract), 2.7 cm posterior to LV at mid-level, 3.1 cm at LV apex from A4C, 3.0 cm at RV apex) (figure 3). Fibrin strands were visible within the pericardium. There was two-dimensional (RVOT compression/collapse, LV compression/failure to expand during diastole, septal flattening/bounce) and Doppler evidence of haemodynamic compromise (RVOT=16%).

Figure 3.

Echocardiogram of the patient’s heart (anonymised). A large haemopericardium can be seen surrounding the ventricles, which have decreased in size as a result of the ongoing compression, leading to the clinical presentation of tamponade.

Differential diagnosis

Given the presentation of abdominal distention and tenderness, the initial differential to be excluded was bowel obstruction with perforation, which was supported by haemodynamic compromise and history of pseudo-obstruction requiring admission earlier in the year. This led to a CT abdomen and pelvis, the imaging gold standard to rule out bowel obstruction and perforation. However, with his oxygen requirement, distended neck veins and tachycardia on a background of complex cardiac issues, a CT chest was included to rule out a cardiac cause, particularly tamponade.

As he was a patient with congenital heart disease, there was concern about recurrence or adult complications, but there was no audible murmur or recent cardiac history. There were also no signs of heart failure, including no peripheral oedema or ascites and no chronic exertional shortness of breath.

The CT chest, abdomen and pelvis performed excluded intra-abdominal pathology and identified the hemopericardium. Therefore, he had an echo which further excluded congenital heart disease complications and helped define the haemopericardium fully.

The reviewing haematologist suggested a specific coagulation screen and factor assay, which identified deficiency in vitamin K dependent factors. This was treated with IV vitamin K, with an improvement in prothrombin time confirming a vitamin K deficiency.

The cause of the vitamin K deficiency has not been conclusively identified. One possibility is that given the patient’s history of abdominal issues and chronic constipation and a previous diagnosis of small intestinal bacterial overgrowth (SIBO), his vitamin K deficiency could be multifactorial, secondary to poor oral intake, small bowel pseudo-obstruction and SIBO. The patient had been treated for his SIBO with ciprofloxacin, which has been linked to vitamin K deficiency and could be another contributing factor, as discussed below.

An additional concern arose regarding the splenic lesions on the initial CT scan that diagnosed the haemopericardium. The patient was found to be globally immunoglobulin deficient, which raised suspicion for potential haematological malignancy or congenital bleeding risk factors. However, after further investigation and immunology input, no evidence for any congenital clotting abnormality or haematological malignancy was found.

Treatment

The patient was treated with two units of fresh frozen plasma before his transfer to a specialist cardiothoracic centre, where he underwent emergency pericardiocentesis and had 800 mL of blood-stained pericardial effusion fluid drained. He had a pericardial drain inserted, which was later removed when his echo indicated that his pericardial effusion had stabilised. He was prescribed colchicine 500 μg once daily for 3 months to manage any underlying myopericarditis and reduce the possibility of a pericardial effusion recurrence. His vitamin K deficiency was corrected with IV vitamin K supplementation.

Outcome and follow-up

After treatment at the local specialist cardiothoracic centre, the patient was repatriated and discharged after his gastrointestinal problems were managed. He had a repeat echo 3 months postdischarge, which showed no reaccumulation of pericardial fluid. He was referred to immunology for further investigation of his ongoing panhypogammaglobulinaemia. Haematology requested that the patient’s clotting, including vitamin K, is checked every 2–3 months in the community. As cardiac tamponade can recur in 10% of patients, close follow-up of patients who have been treated for tamponade after discharge from hospital is paramount.⁴

Discussion

Cardiac abnormalities are present in 75%–80% of individuals with CFC,¹ but this is the first case report of a patient with CFC developing haemopericardium. In our case, bleeding predisposition was caused by vitamin K deficiency. Patients with CFC have been reported to have severe feeding issues and GI complications including dysmotility, intestinal malrotation and constipation, which could affect vitamin K absorption.¹

Vitamin K acts as an integral cofactor for the synthesis of coagulation protein factors II, VII, X and protein C and S. Vitamin K deficiency results in reduced levels of vitamin K dependent clotting factors, thus leading to abnormal clotting tests and a generalised bleeding tendency.⁵

Vitamin K deficiency is uncommon in adults. It can occur due to poor dietary intake, conditions such as liver disease andcystic fibrosis and pharmacotherapy.⁶ In adults without other haematological conditions, all other case reports of spontaneous haemopericardium have been secondary to DOACs (direct oral anticoagulants) or warfarin therapy.^7–14 This is the first case of vitamin K deficiency leading to haemopericardium in an adult not secondary to anticoagulation therapy.

The only other case report of haemopericardium secondary to vitamin K deficiency was in an infant despite prophylactic vitamin K, which is routinely administrated to neonates.¹⁵ The infant had deranged liver function tests and low levels of α1-antitrypsin, thereby undergoing genetic testing which identified α1-antitrypsin deficiency. Due to this underlying disorder, prophylactic vitamin K administered at birth was not absorbed and subsequently vitamin K deficiency occurred. CFC can also cause malabsorption, thus highlighting that Vitamin K deficiency can occur when patients have conditions affecting gut absorption and can suffer serious complications such as haemopericardium.

A case report identified a child with chronic duodenal obstruction and bacterial overgrowth who presented with an unexplained bleeding tendency, ultimately found to be due to malabsorption of fat-soluble vitamins.¹⁶ Similarly to our case, clotting assays improved on administration of parenteral vitamin K. This further illustrates that chronic SIBO can lead to vitamin K deficiency.

The patient had a history of SIBO treated with ciprofloxacin. A case series found an interaction between ciprofloxacin and warfarin, causing an exaggerated hypoprothrombinaemic response in a group of patients who had a bleeding event on average 5.5 days after a course of ciprofloxacin.¹⁷ Warfarin competitively inhibits vitamin K epoxide reductase complex 1, an enzyme activating vitamin K, thereby diminishing vitamin K levels and mimicking vitamin K deficiency.¹³ Ciprofloxacin causing prolonged INR has not been widely reported in patients not taking anticoagulation.

Two cases have been reported of cystic fibrosis patients with increased INR and APTT taking ciprofloxacin, which was reversed on discontinuation of the drug. These patients may have been vitamin K deficient due to pancreatic insufficiency secondary to their underlying disease,¹⁸ but we can reasonably assume that ciprofloxacin may have exacerbated an underlying vitamin K deficiency in our patient.

Our patient’s vitamin K deficiency is likely multifactorial from malabsorption due to chronic intestinal pseudo-obstruction, small bowel obstruction, SIBO and possibly exacerbated by subsequent ciprofloxacin use. Patients with CFC may be predisposed to vitamin K deficiency due to the gastrointestinal manifestations of the disease. Haemopericardium is a rare and life-threatening complication of this deficiency. Initial emergency pericardial drainage is essential to prevent progression to cardiac tamponade and cardiac arrest. However, identifying the underlying cause can help prevent recurrence and progression. In patients with an unexplained bleeding tendency, early input from haematology is paramount and a full coagulation screen and factor assay can identify causes and allow timely management.

Learning points.

• In patients with spontaneous haemopericardium do a full screen of clotting factors and vitamin K levels to investigate for underlying clotting abnormalities.

• Acknowledge that patients may have an underlying vitamin K deficiency even when not on anticoagulation.

• Check vitamin K levels in the community if a patient has had a complication of vitamin K deficiency.

• In patients with vitamin K deficiency not on anticoagulation, enquire about recent antibiotic therapy or other medications interacting with intestinal absorption.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).