Hemorrhagic Cystitis

Overview

Hemorrhagic cystitis is inflammation of the bladder lining accompanied by bleeding into the urine. Unlike typical cystitis caused by bacterial infection, hemorrhagic cystitis involves direct damage to the blood vessels within the bladder wall, producing hematuria that ranges from microscopic amounts detectable only on testing to severe, life-threatening hemorrhage requiring emergency intervention.

The condition most commonly develops as a complication of certain chemotherapy drugs, particularly cyclophosphamide and ifosfamide. These medications produce a toxic metabolite called acrolein that the kidneys excrete into the urine, where it damages the bladder’s protective lining. Hemorrhagic cystitis also occurs in immunocompromised patients when viruses such as BK polyomavirus or adenovirus attack the bladder, and it can develop as a late complication of pelvic radiation therapy.

Grades of Severity

Hemorrhagic cystitis is classified into four grades that guide treatment decisions:

Grade 1 (Mild) involves microscopic hematuria detectable only through urine testing. Patients may have urinary symptoms but no visible blood.

Grade 2 (Moderate) produces visible (gross) hematuria without blood clots. The urine appears pink, red, or tea-colored.

Grade 3 (Severe) causes gross hematuria with blood clots. Clots may obstruct urinary flow and require manual evacuation.

Grade 4 (Life-threatening) presents with massive hemorrhage causing hemodynamic instability. Patients require urgent intervention and blood transfusions.

Symptoms

Early symptoms resemble those of a urinary tract infection and include burning or stinging during urination (dysuria), frequent urination, and sudden urgency. Patients often notice mild pressure or aching above the pubic bone.

As the condition progresses, visible blood appears in the urine. The color ranges from light pink to dark red depending on severity. Bladder spasms produce painful cramping sensations. Blood clots may form, and when large enough, they can obstruct the urethra and cause urinary retention—an inability to empty the bladder despite a strong urge. Patients often wake multiple times at night to urinate.

In severe cases (Grade 3-4), patients pass large clots and experience significant blood loss. Signs of anemia develop: fatigue, weakness, pale skin, and rapid heartbeat. Intense lower abdominal pain occurs. Severe hemorrhage can cause dizziness and low blood pressure, signaling hemodynamic instability that requires emergency care.

Causes

Chemotherapy-induced hemorrhagic cystitis is the most common form. Cyclophosphamide, used to treat lymphoma, leukemia, breast cancer, and autoimmune conditions, produces acrolein as a metabolite. This compound is highly toxic to the bladder lining. Without preventive measures, 2-40% of patients receiving cyclophosphamide develop hemorrhagic cystitis. Ifosfamide works through a similar mechanism but carries even higher risk—up to 40% of patients without prevention. Other chemotherapy drugs implicated include busulfan (used in bone marrow transplant conditioning), temozolomide, thiotepa, and high-dose methotrexate.

Viral hemorrhagic cystitis particularly affects immunocompromised patients. BK polyomavirus is the most common viral cause, affecting 5-25% of bone marrow transplant recipients typically 2-8 weeks after transplant. BK virus infection can cause severe, prolonged bleeding and carries significant mortality risk when severe. Adenovirus (especially types 7, 11, 34, and 35) affects both children and adults and can cause severe hemorrhage. Other viral causes include cytomegalovirus and JC virus.

Radiation-induced hemorrhagic cystitis develops as a late complication of pelvic radiation therapy, sometimes appearing months to years after treatment. The radiation damages blood vessels in the bladder wall, causing them to become fragile and prone to bleeding. See our dedicated page on radiation cystitis for detailed information.

Other causes include industrial chemical exposure (aniline dyes, toluidine, the pesticide chlordimeform) and rarely certain medications such as tiaprofenic acid, penicillins, and danazol.

Risk factors include previous episodes of hemorrhagic cystitis, pre-existing bladder conditions, dehydration during chemotherapy, immunocompromised state, previous pelvic radiation, older age, and female sex. High-dose chemotherapy, prolonged treatment, inadequate hydration, and failure to use preventive medications increase risk substantially.

Diagnosis

Diagnosis begins with a detailed medication and treatment history, particularly the timing of symptoms relative to chemotherapy or transplant. Clinicians assess symptom severity and review what preventive measures were used.

Physical examination evaluates the abdomen for bladder distension and suprapubic tenderness, checks for signs of anemia (pallor, rapid pulse), and monitors vital signs for hemodynamic stability.

Laboratory tests include urinalysis to confirm blood and rule out bacterial infection, urine culture to exclude bacterial cystitis, and complete blood count to monitor hemoglobin levels and assess for anemia. For immunocompromised patients, viral studies include BK virus and adenovirus PCR testing. Coagulation studies rule out bleeding disorders that might contribute to hemorrhage.

Imaging with ultrasound assesses bladder wall thickness, identifies clots, and measures post-void residual volume. CT scanning rules out other causes of hematuria and evaluates the upper urinary tract.

Cystoscopy (direct visualization of the bladder) may be performed when diagnosis is uncertain, when other causes of hematuria must be excluded such as bladder cancer, or when therapeutic intervention is needed. Typical findings include diffuse bleeding from the bladder mucosa, edema, dilated blood vessels (telangiectasias), blood clots, and ulceration in severe cases.

Treatment

Prevention is the most important aspect of management for patients receiving cyclophosphamide or ifosfamide. Mesna (2-mercaptoethane sulfonate) binds and neutralizes acrolein in the urine and reduces incidence by 80-90%. It is administered before, during, and after chemotherapy and is the standard of care for ifosfamide. Aggressive IV hydration before, during, and after chemotherapy maintains high urine output (>100 mL/hour) and dilutes toxic metabolites. Frequent voiding every 2-3 hours, including through the night if possible, prevents prolonged contact of toxins with the bladder. In high-risk settings, continuous bladder irrigation may be used during chemotherapy.

Grade 1 treatment focuses on increased fluid intake, close monitoring, continued mesna if on chemotherapy, and supportive care. Most mild cases resolve spontaneously.

Grade 2 treatment requires aggressive IV hydration and continuous bladder irrigation with saline. Hemoglobin is monitored closely, pain is managed, and chemotherapy may be adjusted or discontinued if possible.

Grade 3 treatment involves continuous bladder irrigation using a three-way catheter, manual clot evacuation if needed, blood transfusions to maintain hemoglobin, and cystoscopy for clot evacuation and fulguration (cauterization) of bleeding vessels. Intravesical treatments may be initiated.

Grade 4 treatment requires intensive care monitoring, aggressive blood product support, emergent cystoscopy with fulguration, intravesical hemostatic agents, and consideration of embolization or surgery.

Intravesical therapy instills medications directly into the bladder. Options include aminocaproic acid (inhibits fibrinolysis), alum (causes protein precipitation and vasoconstriction), silver nitrate (chemical cauterization for severe cases), formalin (last-resort agent with significant complication risk), and prostaglandins such as carboprost.

Hyperbaric oxygen therapy promotes healing through increased tissue oxygenation and stimulates new blood vessel formation. It typically requires 20-40 sessions and reports success rates of 60-80% for chronic or refractory cases.

Viral hemorrhagic cystitis treatment focuses on reducing immunosuppression if possible, antiviral medications (cidofovir IV or intravesical, leflunomide for BK virus; cidofovir or brincidofovir for adenovirus), and supportive care.

Surgical intervention is reserved for severe, refractory cases. Selective embolization through interventional radiology blocks bleeding vessels while preserving bladder function. Cystectomy with urinary diversion (bladder removal with creation of an alternative urinary pathway) is the last resort for life-threatening, uncontrollable bleeding.

Prevention

Patients receiving cyclophosphamide or ifosfamide should ensure adequate hydration before treatment, empty their bladder before receiving chemotherapy, and confirm mesna will be given. During treatment, maintain high fluid intake, follow the mesna schedule precisely, and report any urinary symptoms immediately. After treatment, continue drinking extra fluids for 24-48 hours, urinate frequently, complete all prescribed mesna doses, and avoid bladder irritants such as caffeine and alcohol.

Bone marrow transplant recipients should maintain hydration protocols, undergo early viral screening for BK virus and adenovirus, report any urinary symptoms promptly, and follow infection prevention guidelines.

General prevention measures include staying well hydrated, avoiding smoking (which damages blood vessels), limiting bladder irritants, and emptying the bladder completely and regularly.

When to See a Doctor

Contact your healthcare provider if you notice any blood in your urine during or after chemotherapy, experience burning or pain with urination, urinate more frequently than normal, have difficulty emptying your bladder, or feel lower abdominal pain or pressure.

Seek urgent medical attention for significant visible blood in urine, blood clots in urine, inability to urinate, signs of blood loss (dizziness, weakness, rapid heartbeat, pale skin), severe pain not controlled by prescribed medications, or fever with urinary symptoms.

If you are receiving or have recently received cyclophosphamide, ifosfamide, or other high-risk chemotherapy, report any urinary symptoms immediately—even mild ones. Early intervention prevents progression to more severe hemorrhagic cystitis. Prevention through proper hydration and mesna protocols is far more effective than treating established disease.