Left gonadal vein thrombosis in a patient with COVID-19-associated coagulopathy.

COVID-19 disease is a viral illness that predominantly causes pneumonia and severe acute respiratory distress syndrome. The endothelial injury and hypercoagulability secondary to the inflammatory response predisposes severely ill patients to venous thromboembolism. The exact mechanism of hypercoagulability is still under investigation, but it is known to be associated with poor prognosis. The most common thrombotic complication reported among these patients is pulmonary embolism. To our knowledge, gonadal vein thrombosis is an uncommon phenomenon that has not been reported in the setting of COVID-19-associated coagulopathy. We report an unusual case of ovarian vein thrombosis and pulmonary embolism associated with COVID-19 presenting with abdominal pain. To our knowledge, this is the first reported case of COVID-19 with absent respiratory symptoms and presentation with venous thrombosis in an unusual location. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Background

Since the emergence of SARS-CoV-2 in December 2019, the world has faced an unprecedented public health crisis due to its high rate of transmission and the broad spectrum of the disease severity. The manifestation of the disease ranges from asymptomatic carriers to severe acute respiratory distress syndrome requiring mechanical ventilation and intensive care unit (ICU) admission. The severe cases are more prone to arterial and venous thrombosis. These thrombotic events have been related to poor prognosis and linked to unexpected cardiac deaths.1

The pathophysiology of thrombosis in COVID-19 is hypothesised to be due to a hypercoagulable state from excessive inflammation, hypoxia, immobilisation and in severe cases of disseminated intravascular coagulation.2 The most common location of thrombosis is pulmonary arteries. Other reported venous thromboembolisms (VTEs) include lower extremity thrombosis and catheter-associated thrombi.3

Ovarian vein thrombosis (OVT) is a rare and potentially fatal condition of postpartum period, which can act as a source of pulmonary embolism.4 5 Gonadal vein thrombosis has never been reported during this pandemic as a result of COVID-19. We present a unique case which demonstrates left gonadal vein thrombosis secondary to COVID-19 as the first presenting sign.

Case presentation

A 52-year-old postmenopausal woman, with no known medical history, presented to our hospital with sudden onset of severe sharp right upper quadrant abdominal pain for 2 days. She described the pain to be unrelated to food and not associated with any other gastrointestinal (GI)-related symptoms.

She denied recent fevers, cough or upper respiratory tract infection symptoms. She was afebrile (temp 97.7°F), pulse rate 93 beats/min, respiratory rate 22/min and oxygen saturation was 94% on room air, body mass index 29 kg/m2. Her physical examination on admission was notable for shallow breathing, clear lungs and non-tender abdomen.

Investigations

The labs were significant for increased inflammatory markers, including ferritin (883 µg/L), C reactive protein (217 mg/L) and D-dimer was markedly elevated to 3813 ng/mL (table 1).

Table 1

The patient’s laboratory findings on admission

Labs	On admission	Normal range
WBC	15.10	3.5–11x109/L
Neutrophil count	12.72	1.7–9x109/L
Lymphocyte count	1.39	1.2–3.5x109/L
PLT	467	150–440x109/L
PT	16.1	9.4–12.5 s
PTT	27.9	25.1–36.5 s
INR	1.4	0.8–1.1 ratio
C reactive protein	217	0–5 mg/L
Ferritin	719	12–150 µg/L
LDH	386	100–210 U/L
D-dimer	3813	0–230 ng/mL
Fibrinogen	883	200–400 mg/dL

INR, international normalised ratio; LDH, lactate dehydrogenase; PLT, platelets; PT, prothrombin time; PTT, partial thromboplastin time; WBC, white blood cells.

Chest X-ray showed patchy peripheral densities seen in the upper lobe on the frontal view. On the lateral view there were patchy infiltrates posteriorly in the lower lobes suggestive of COVID-19.

CT of the abdomen/pelvis with contrast showed left OVT, which extended partially to the renal vein (figures 1 and 2). Additionally, there was a finding of pulmonary embolism in the posterior branch of pulmonary artery in the right lower lobe (RLL). Pulmonary windows of the CT confirmed presence of bilateral lower lobe consolidations, ground-glass opacities in the right middle lobe and foci of consolidation in the lingula suggestive of COVID-19 pneumonia. Subsequent chest CT angiography confirmed the presence of an acute RLL pulmonary artery thrombosis (figure 3). Deep vein thrombosis (DVT) studies were negative for lower extremity venous clots.

Figure 3

Acute right lower lobe pulmonary embolism—mild bilateral lower lobe consolidations suggestive of COVID-19 pneumonia.

Coronal view of thrombosis in the left gonadal vein with extension to the left renal vein.

Axial view of thrombosis in the left gonadal vein with extension to the left renal vein.

Nasopharyngeal swab confirmed the diagnosis of COVID-19. Echocardiography showed normal biventricular systolic function in the absence of right heart strain.

Differential diagnosis

To further investigate secondary causes of hypercoagulability, rheumatologic panel including antinuclear antibody–extractable nuclear antigen panel, lupus anticoagulant, protein C, protein S and antithrombin III were tested and resulted negative. Tumour markers, including carcinoembryonic antigen, carbohydrate antigen 9/19 and cancer antigen-125 were negative and the initial CT scan of chest/abdomen/pelvis was without any evidence of malignancy. COVID-19 was deemed to be the provoking cause of the thrombosis.

Treatment

The patient was started on therapeutic low molecular weight heparin (enoxaparin) 1 mg/kg two times per day, which resulted in significant improvement of the abdominal pain few hours after the first dose. She remained afebrile, denied any cough or shortness of breath, and oxygen saturation remained stable on room air. She was discharged after 3 days of hospitalisation on apixaban 10 mg two times per day for a week, followed by 5 mg two times per day for 3 months.

Outcome and follow-up

During follow-up after a month, the patient reported mild abdominal pain, but remained afebrile and without any respiratory symptoms. She denied any bleeding complication. A repeat CT of the abdomen and pelvis showed resolution of thrombosis. D-dimer at the follow-up visit was 234 ng/mL.

Discussion

The COVID-19 pandemic caused by the SARS-CoV-2 has affected millions of people worldwide. While a majority of the people affected by the virus remain asymptomatic, most patients admitted to the hospital present with severe respiratory illness. The most extensive published case series from China and New York report that the majority of patients present with fever, cough, fatigue and GI symptoms.6 7 Nearly 20% of these patients present with severe coagulation abnormalities. But rarely, VTE may be the initial presenting feature in patients with SARS-CoV-2 infection.8 Concomitant VTE, a potential cause of unexplained deaths, has been frequently reported in COVID-19 cases.8 9 Our patient was distinctive in terms of presentation as she lacked the common respiratory symptoms, rather acute venous thrombosis in an unusual location prompted the diagnosis of COVID-19.

Virchow’s triad defined as blood stasis, endothelial injury and a hypercoagulable state leads to the pathogenesis of thrombosis.10 Patients with COVID-19 usually present with dehydration and prolonged bed rest, which are risk factors for blood stasis.11 SARS-CoV-2 infects ACE 2 receptors, which is present on multiple organs, including the endothelial cells. In a recent study on postmortem autopsies, there was evidence of endothelitis caused by either direct viral invasion of the endothelial cells or endothelial injury derived from the inflammatory response. This possibly explains why patients with endothelial dysfunction due to pre-existing conditions are more prone to organ failure secondary to microthrombi and present with a more severe form of the illness.12 Also, the COVID-19 infection can cause a severe inflammatory response, which results in the release of cytokines such as interleukin 6, tumour necrosis factor-alpha. 13 These cytokines stimulate the activation of the coagulation cascade and increase the risk of VTE.14 Other proposed pathophysiology behind an increased propensity to thrombosis is the finding of antiphospholipid antibodies, which can transiently arise in patients with critical illness and various infections and potentially contribute to a hypercoagulable state.15 16

Based on the available literature, most thrombotic events in COVID-19, including pulmonary embolism or DVTs, develop in critically ill patients with severe pulmonary disease.2 17 18

Our case was unique as she had no respiratory symptoms and an otherwise uncomplicated clinical course; however, she still presented with a thrombotic complication in an unusual site.

OVT is a rare entity that is most commonly seen in the postpartum period. Other causes of OVT include pelvic inflammatory disease, recent gynaecological or abdominal surgery, hypercoagulable state and underlying malignancy.5 An underlying hypercoagulable state has been reported in 50% of the cases with OVT.19 Regardless of the aetiology, right-sided OVT accounts for 70%–90% of the cases. It can likely be related to dextrotorsion of the uterus that compresses the right ovarian vein, antegrade flow and relatively more incompetent valves of the right ovarian vein.20 The most common symptoms are fever (80%) and right-sided pelvic pain (55%).21 Our patient was unusual as she did not have a fever on presentation, and the venous thrombosis was on the left side. This condition can be fatal due to the serious life-threatening complication from thrombus extension into the systemic veins and subsequent pulmonary artery embolisation. The incidence of OVT complicated by pulmonary embolism is reported to be approximately 25%.22 Our case was diagnosed with OVT and subsequent pulmonary embolism. It is unclear if the pulmonary embolus occurred secondary to embolisation of ovarian thrombosis or a primary thrombus as a result of hypercoagulability state due to COVID-19, specifically in the absence of lower extremity DVT. The treatment for OVT is anticoagulation for 3–6 months. However, no clear guideline is available about the duration of therapy, and non-vitamin K antagonist oral anticoagulants have not yet been studied in such cases.5 20

The only widely available treatment in COVID-19-associated coagulopathy is prophylactic dose of low molecular weight heparin, which should be considered in all patients (including non-critically ill) who require hospital admission for COVID-19 infection.23

Use of higher-intensity, non-standard anticoagulation currently lacks efficacious evidence in COVID-19.10 A study by Klok et al2 showed a 31% incidence of thrombotic complications in ICU patients with COVID-19 infection despite being on prophylactic anticoagulation. Considering this remarkably high incidence of VTE, it is suggested to increase the intensity of anticoagulation despite the lack of randomised evidence to support the practice. Current evidence suggests D-dimer, an indicator of fibrin breakdown, can be used to assess severity of clot burden and guide initiation and monitoring of therapy.1 24

In summary, we present an interesting case with an unusual presentation of COVID-19 who presented with abdominal pain and no significant respiratory symptoms and was diagnosed with thrombosis of the left ovarian vein. Our case emphasises the high risk of coagulopathy in COVID-19 cases, even without a severe systemic infection. Evaluation and risk stratification for thrombosis with coagulation markers and D-dimer should be incorporated in the management of COVID-19.25

This is the first case report of ovarian vein thrombosis secondary to COVID-19-associated coagulopathy (CAC).

CAC can present with thromboembolic complications even in the absence of typical respiratory symptoms.

CAC is associated with poor prognosis and prompts prophylactic anticoagulation in all patients who require hospitalisation.

Coagulopathy is independently indicative of severe illness even in the absence of lung involvement. Prothrombin time/partial thromboplastin time/international normalised ratio, fibrinogen and D-dimer should be monitored in all patients with COVID-19 requiring hospitalisation.