Hemorrhagic cystitis is defined by severe inflammation of the bladder lining (urothelium) that results in bleeding into the urine. This condition is often a complication of aggressive medical treatments, particularly those targeting cancer. Primary symptoms include blood in the urine (hematuria), which can range from microscopic to visible clots. This is typically accompanied by lower urinary tract issues such as pain or burning during urination and a frequent or urgent need to urinate.
Damage from Chemotherapy Agents
The most frequent cause of hemorrhagic cystitis is chemical toxicity from specific chemotherapy drugs. Agents belonging to the oxazaphosphorine class, primarily cyclophosphamide and ifosfamide, are strongly associated with this complication. These drugs are not directly toxic to the bladder; their toxicity arises after they are metabolized by the liver.
The liver converts these agents into several metabolites, including a highly reactive compound called acrolein. Acrolein is excreted by the kidneys and concentrates within the bladder, where it contacts the urothelium. This toxic metabolite directly damages urothelial cells, triggering inflammation and cell death.
When the protective urothelial layer is destroyed, the underlying blood vessels and connective tissues of the bladder wall become exposed to irritating urine. This exposure leads to ulceration, inflammation, and hemorrhage. The risk is high, occurring in up to 70% of patients who receive high doses of cyclophosphamide or ifosfamide. Specialized medications, like mesna, are often administered preventatively to neutralize acrolein, reducing its toxicity.
Radiation Exposure in the Pelvis
Therapeutic radiation, used to treat pelvic cancers such as prostate, bladder, or cervical cancer, is another major cause. The high-energy radiation damages microscopic structures within the bladder wall, leading to radiation cystitis. This damage typically affects small blood vessels and connective tissue, unlike the immediate chemical irritation caused by chemotherapy.
The mechanism involves progressive obliteration of small blood vessels in the bladder wall, a process called obliterative endarteritis. This damage reduces blood flow, leading to chronic low-oxygen conditions (ischemia) within the bladder tissue. The lack of oxygen causes the bladder lining to weaken and ulcerate, resulting in chronic inflammation and delayed bleeding.
Radiation-induced hemorrhagic cystitis is characterized by delayed onset. It may occur acutely during treatment or, more commonly, months to years after the final radiation dose. This chronic complication can appear as late as two decades following initial radiotherapy. The resulting fibrosis and scarring can also reduce bladder capacity and compliance.
Viral and Microbial Infections
Hemorrhagic cystitis can also be triggered by pathogens, particularly in individuals with compromised immune systems. Specific viruses are the primary infectious culprits, most notably Adenovirus and BK polyomavirus (BKPyV). These viral infections are frequently observed in patients who have undergone bone marrow or stem cell transplantation.
Adenovirus serotypes 11 and 21 can directly infect urothelial cells, causing damage, inflammation, and bleeding. BK polyomavirus, which often lies dormant, can reactivate under immunosuppression. This reactivation leads to viral replication within bladder cells, causing direct cellular damage. This differs from standard bacterial urinary tract infections, which typically cause non-hemorrhagic inflammation.
Less Common Medication and Systemic Factors
Less frequent factors can also result in hemorrhagic cystitis, often involving drug reactions or complex systemic conditions. Certain non-chemotherapy medications, including some antibiotics like penicillins, have been implicated. These drug-induced cases are rare and often involve an immune-mediated hypersensitivity reaction rather than direct chemical toxicity.
Systemic factors, such as complications following allogeneic hematopoietic stem cell transplantation (HSCT), are a trigger. These procedures combine high-dose chemotherapy and intense immunosuppression, creating a high-risk environment. This combination increases the risk of viral reactivation and can lead to graft-versus-host disease (GVHD) effects in the bladder. Rare reports have also linked hemorrhagic cystitis to drugs like the anabolic steroid danazol and certain non-steroidal anti-inflammatory agents.