Bilateral renal haematuria and obstructive renal failure from acquired haemophilia A: a medical cause for a surgical problem

Abstract

A 55-year-old male presented to our emergency department with haematuria and abdominal pain. Investigations including a computed tomography (CT) scan revealed an intraluminal filling defect within the left collecting system, consistent in appearance with blood clot. With an initial working diagnosis of upper tract urothelial cell carcinoma, he was discharged with plans for an urgent cystoscopy and ureteroscopy. He subsequently represented with ongoing frank haematuria, anasarca, dropping haemoglobin and new right collecting system blood clot. Subsequent investigations showed that the patient had acquired haemophilia A resulting in the episodes of haematuria, highlighted after an elevated activated partial thromboplastic time prompted a thrombophilia screen. The patient was subsequently treated with factor eight inhibitor bypass activity, corticosteroids and cyclophosphamide.

Background

Haematuria is a common presenting complaint. Common causes include benign and malignant conditions such as urolithiasis, urinary tract infections (UTIs), malignancy, trauma and prostate hyperplasia. There is limited evidence in the literature of haematuria being the presenting complaint of a primary bleeding disorder. We present a case of a patient with sudden and persistent visible haematuria involving bilateral collecting systems and obstruction who was subsequently diagnosed with acquired haemophilia A.

Case presentation

Initial presentation

A previously asymptomatic 55-year-old El Salvadorian man presented to our emergency department with a 5-day history of rosé-coloured haematuria and lower abdominal pain. He had associated urinary frequency and dysuria. He had no history of trauma, urethral discharge, rashes, testicular pain or swelling, and had no risk factors for sexually transmitted infections. He had no prior personal or family history of malignancy or urolithiasis.

He suffered from type 2 diabetes mellitus, dyslipidaemia and hypertension and was a distant ex-smoker. He denied previous history of bleeding and was never on systemic blood thinners.

Examination revealed an obese gentleman with a soft non-distended abdomen with suprapubic tenderness. No abdominopelvic lymphadenopathy or masses were noted. Per rectal examination revealed a benign, non-enlarged prostate. He had normal external genitalia and was haemodynamically stable and afebrile.

A renal ultrasound demonstrated perinephric-free fluid with prominent lower pole calyces and hyperechogenic areas within the left collecting system (figure 1). Follow-up CT intravenous pyelogram confirmed the presence of intraluminal filling defect within the left renal tract with heterogenous hyperattenuation consistent with a blood clot (figure 2). His urine sample showed >500×10⁶/L erythrocytes, >500×10⁶/L leucocytes and <10×10⁶/L epithelial cells, with no bacterial growth. Urine cytology showed no malignant cells. Serum prostate specific antigen was 0.87 µg/L. His haemoglobin (Hb) on presentation was 119 g/L with a white cell count of 7.8×10⁹/L. Renal function tests showed postrenal acute kidney injury (AKI) with a serum creatinine of 125 μmol/L and estimated glomerular filtration rate of 56 mL/min/1.73 m². He also had an elevated activated partial thromboplastic time (APTT) of 50.

Figure 1.

Ultrasound kidneys, ureters and bladder (US KUB) showing left echogenic foci suggestive of blood clot.

Figure 2.

CT intravenous pyelogram showing left intraluminal hyperdense substance with no contrast excretion demonstrating obstruction.

The working diagnosis at the time was a UTI with haemorrhagic pyelitis, although the suspicion was raised regarding a possible underlying urothelial lesion involving the left collecting system. He was initially treated conservatively with 5 days of intravenous ceftriaxone and fluids and was discharged once his haematuria and AKI resolved with a plan for rigid cystoscopy and diagnostic ureteroscopy. Arrangements were also made for haematology follow-up regarding the raised APTT.

Representation

He represented 1 month later with an Hb of 67 g/L. He had redeveloped frank haematuria, contralateral flank pain, anasarca and nephrotic range proteinuria (urine protein 7300 mg/L and urine protein to creatinine ratio of 672 g/mol). A non-contrast CT KUB showed intraluminal hyperdensity, now within the right collecting system, likely due to blood products within the right renal pelvis and ureter. Given the new onset proteinuria and renal impairment, the working diagnosis changed to glomerulonephropathy (GN).

The patient underwent a complete GN screen, including:

• Complement C3/4 (within normal limits).

• Antinuclear antibody (ANA; positive, speckled).

• Anti-neutrophil cytoplasmic antibody (ANCA)/Extractable nuclear antigen (ENA)/Rheumatoid factor (RF)/anti-cyclic citrullinated peptide (anti-CCP)/serum protein electrophoresis (all negative).

• Human immunodeficiency virus (HIV)/Hepatitis B virus (HBV)/Hepatitis C virus (HCV) (all negative).

• Anti-glomerular basement membrane (anti-GBM) screen (negative).

• Symmetrical elevated free to light chains (FLC) ratio.

Given the negative GN screen, the cause of the patient’s haematuria was again felt to be urological in nature. A Technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) scan was performed due to persisting AKI secondary to known blood in the right collecting system, showing a non-functioning right kidney with renal differential function approaching 0%, and a normal functioning left kidney (figure 3). He underwent inpatient exploratory cystoscopy and ureteroscopy.

Figure 3.

MAG3 scan demonstrating pooling of contrast in the right kidney without outflow. The left kidney is draining normally.

Intraoperatively, dissolving clots were visible with several telangiectasic lesions on cystoscopy. The retropyelogram (RPG) showed a large right filling defect with a ‘moth-eaten’ appearance of distal ureter on RPG (figure 4). The left side was normal on ureteroscopy and RPG. Right side ureteroscopy showed non-specific inflammation of ureteric mucosa, broadening the working diagnosis to include uncommon cases such as amyloid, schistosomiasis, tuberculosis and malakoplakia. The left sided system had a normal RPG and the previously identified filling defect had resolved. Biopsies of the lesions, washings and urine acid-fast bacilli were all negative.

Figure 4.

Moth-eaten appearance of right distal ureter of retrograde pyelogram.

The patient subsequently complained of tingling, numbness and severe pain in the left hand, which was the site of a previous intravenous cannula in the left antecubital fossa. Concerns were raised for compartment syndrome, with the patient undergoing an emergency fasciotomy, revealing a large antecubital fossa haematoma. Our haematology service was reconsulted for a rising APTT of 131 (noted to be 50 on his previous admission). A thrombophilia screen was subsequently performed, consisting of a positive lupus anticoagulant and lower-than-normal chromogenic factor VIII assay of 0.3 (reference range 0.5–1.5) with positive factor VIII inhibitor at 12.5 BU/mL (Bethesda method). This supported the diagnosis of progressive acquired thrombophilia A (AHA) masked by a positive lupus anticoagulant.

Treatment

Treatment was initiated with recombinant factor VIIa (NovoSeven) 8 mg every 2 hours, which did not achieve adequate haemostatis. The patient was switched to factor eight inhibitor bypass activity (FEIBA) 4000 units 6 hourly, oral cyclophosphamide 50 mg twice daily and oral prednisolone 1 mg/kg to suppress factor VIII inhibitor production.

Outcome and follow-up

The patient remains an inpatient at our institute, being managed for a new diagnosis of Parkinson’s disease in addition to cholelithiasis, while receiving ongoing FEIBA, corticosteroids and cyclophosphamide. His renal function was noted to return to baseline with resolution of his hematuria.

Discussion

Haematuria is a common urological complaint with multiple aetiologies including UTIs, renal calculi, renal parenchymal disease and malignancies. In addition to these common causes for haematuria, urologists should consider other uncommon conditions such as atypical infections, inflammatory diseases, GN and AHA when faced with recurrent and persistent haematuria involving bilateral renal systems.

AHA is a disorder arising from autoantibodies against factor VIII. This results in impaired activation of the intrinsic coagulation cascade, resulting in potentially life-threatening haemorrhage. Concerningly, however, this condition is diagnosed late and often in the setting of severe symptomatic haemorrhage, as with our patient. Therefore, there is a high mortality associated with this condition, ranging between 9.7% and 33%. The rarity of the presentation also contributes to the delay in diagnosis, with Hosier et al suggesting that only eight cases have been described in the literature.¹

Diagnosis of this condition is made in conjunction with a prolonged activated partial thromboplastin time along with low titres of factor VIII levels. Often, a normal prothrombin time is noted as the extrinsic coagulation pathway is unaffected.² The cornerstone of treatment in AHA is immunosuppression to eradicate antibodies and ensuring adequate haemostasis. Antibody eradication is typically achieved by immunosuppression. Data from the European Acquired Haemophilia (EACH2) registry, a multicentre, European database of AHA patients, suggest that the optimal immunosuppression regime is a combination of cyclophosphamide along with steroids.³

Haemostasis is typically achieved by administration of bypassing agents, which promote clotting by circumventing the need for factor VIII in the clotting cascade. This is typically achieved by either activated prothrombin complex concentrate (marketed as FEIBA) or recombinant activated factor VII (marketed as NovoSeven). Both agents result in the generation of thrombin, thereby achieving haemostasis.³ Either agent can be used as first-line therapy, and should haemostasis fail to be achieved, the alternative agent is typically employed.⁴

Despite treatment with adequate therapy, relapse remains a distinct possibility. In the EACH2 registry, approximately 12% of patients who were treated with a combination of cyclophosphamide and steroids relapsed and had a recurrence of their symptoms. Relapse was seen in 139 days in patients relapsing on combination therapy.⁵ Therefore, monitoring for relapse is as important as eradication treatment and achieving haemostasis in these patients.

Learning points.

• Haematuria is a common urological complaint which is can be caused by urolithiasis, urinary tract infections, malignancy, trauma and prostatic hyperplasia.

• In addition to the more commonly encountered causes of haematuria, other uncommon causes should be considered when it involves bilateral collecting systems such as glomerulonephropathy and coagulopathy (in this case, acquired haemophilia A (AHA)).

• AHA, if not promptly managed, has a high morbidity and mortality.