Thrombotic thrombocytopenic purpura is an uncommon but potentially deadly form of thrombotic microangiopathy, a family of disorders in which small blood vessels become obstructed by clots. In its classic form, TTP produces a constellation of findings: microangiopathic hemolytic anemia, in which red blood cells are sheared apart as they squeeze through partially blocked vessels; severe depletion of platelets, the cell fragments that form clots; neurological abnormalities; kidney injury; and fever. The immune-mediated variant of the disease, known as iTTP, arises when the body produces autoantibodies that either inhibit or clear ADAMTS13, an enzyme whose job is to trim oversized strands of von Willebrand factor (VWF), a protein that helps platelets stick together.

When ADAMTS13 is knocked out of commission, these oversized VWF strands accumulate unchecked in the bloodstream. Platelets bind to them indiscriminately, forming microthrombi that clog capillaries throughout the body. Red blood cells are forced through the narrowed passages and are physically torn apart, producing the fragmented cells — schistocytes — that pathologists recognize under the microscope. The result is a cascade of anemia, platelet depletion, and oxygen starvation of vital organs, particularly the brain, kidneys, and heart. Without urgent treatment, mortality rates historically approached 90 percent.

For the 45-year-old African-American woman at the center of this report, the diagnosis unfolded with textbook speed but devastating severity. She arrived at the emergency department with several hours of transient expressive aphasia — difficulty producing speech — along with blurred vision and dizziness. Initial bloodwork revealed a hemoglobin level of 6.3 grams per deciliter, far below the normal range, and a platelet count of just 21,000 per microliter, roughly one-twentieth of normal. Her haptoglobin, a protein that binds free hemoglobin released from destroyed red cells, was undetectable, and her lactate dehydrogenase, a marker of cell damage, was markedly elevated at 1,078 units per liter. A peripheral blood smear confirmed the presence of schistocytes, sealing the diagnosis of microangiopathic hemolytic anemia.

Clinicians calculated a PLASMIC score — a validated tool for estimating the likelihood of TTP in patients with unexplained hemolysis and thrombocytopenia — and it came back at 6 points, placing the patient in the high-probability category. Two days later, confirmatory testing revealed an ADAMTS13 activity level below 5 percent of normal, alongside a positive inhibitor screen with a Bethesda titer of 4.2 Bethesda units per milliliter, confirming that autoantibodies were actively neutralizing the enzyme. The diagnosis of immune-mediated TTP was definitive. Treatment with high-dose intravenous methylprednisolone, a potent corticosteroid, was initiated immediately, and the hematology team strongly recommended urgent plasma exchange, the traditional cornerstone of TTP therapy that physically removes the offending antibodies from the bloodstream while replacing ADAMTS13-rich donor plasma.

But the patient and her husband, devout Jehovah’s Witnesses, declined plasma exchange on religious grounds. Their faith, as they understand it, prohibits the transfusion of whole blood, red blood cells, white blood cells, platelets, and plasma. While certain fractionated blood products such as albumin, clotting factors, and immunoglobulins are matters of personal conscience rather than absolute prohibition, the couple declined both conventional plasma exchange and an alternative approach using albumin-based plasmapheresis. The medical team was forced to chart an entirely different course.

On day three of hospitalization, the patient received rituximab, a monoclonal antibody that depletes the B cells responsible for producing the autoantibodies against ADAMTS13. Urgent efforts were made to obtain caplacizumab, a humanized antibody fragment that binds to the A1 domain of von Willebrand factor, physically blocking platelets from attaching to it and thereby preventing the formation of new microvascular thrombi. The drug, approved by the FDA in 2019 for use in combination with plasma exchange, had never before been tested in a patient with TTP this severe — with neurological compromise requiring intubation and hemoglobin levels this profoundly depressed.

By day four, the patient’s condition had deteriorated dramatically. Her hemoglobin had fallen to 5.4 grams per deciliter and would eventually bottom out at 3.8, her platelet count dropped to 9,000 per microliter, and she became unresponsive, requiring emergency intubation and transfer to the intensive care unit. Elevated troponin levels signaled cardiac injury, and her kidneys and liver were showing signs of compromise. Caplacizumab was administered immediately upon arrival — 11 milligrams intravenously, followed by 11 milligrams subcutaneously daily. A trial of plasmapheresis with albumin replacement was attempted but abandoned when the machine began alarming due to the patient’s critically low hematocrit, which had fallen to between 11 and 16 percent, and the effluent became turbid with hemolytic debris. The patient also began oozing significantly from the access site, raising concerns that continued albumin-based plasma exchange would worsen bleeding.

The clinical turnaround was striking. On day five, the medical team added intravenous folic acid and subcutaneous epoetin alfa, an erythropoiesis-stimulating agent that prompts the bone marrow to produce new red blood cells, along with intravenous immune globulin at 1,000 milligrams per kilogram daily for two doses, which the patient’s husband consented to. By day six, her platelet count had rebounded to 48,000 per microliter, her haptoglobin had risen to 10 milligrams per deciliter, and her neurological status improved so dramatically that she was successfully extubated. By day seven, her neurological symptoms had completely resolved. On day nine — after just six doses of caplacizumab and without any plasma exchange — she achieved clinical remission, defined as two consecutive days with a normal platelet count and a continued downward trend in lactate dehydrogenase. She was discharged from the hospital on day fourteen, continuing daily subcutaneous caplacizumab at home alongside a gradual six-week taper of oral corticosteroids.

Yet the underlying autoimmune attack had not been fully extinguished. One month after caplacizumab initiation, despite corticosteroids, four weekly doses of rituximab, and intravenous immune globulin, the patient’s ADAMTS13 activity remained stubbornly below 5 percent. The medical team escalated to intravenous cyclophosphamide, a powerful chemotherapy agent that suppresses the immune system more broadly. After a single dose of 600 milligrams per square meter, her ADAMTS13 activity normalized to 79 percent. Caplacizumab was discontinued on day fifty of therapy. Cyclophosphamide was stopped after four doses once laboratory values fully normalized — ADAMTS13 activity above 100 percent, platelets at 164,000 per microliter, hemoglobin at 11.9 grams per deciliter, and lactate dehydrogenase at 221 units per liter — with no recurrence of neurological symptoms. She remains in both clinical and immunological remission.

The case, reported by physicians at North Memorial Health in Robbinsdale, Minnesota, and the University of Minnesota, is the first documented use of caplacizumab in a Jehovah’s Witness patient with TTP this severe — with neurological compromise necessitating intubation and hemoglobin levels this low. It adds to a growing body of evidence suggesting that caplacizumab, when initiated early, may be sufficient on its own to manage acute iTTP episodes without plasma exchange. A 2024 study of 42 iTTP episodes in 41 patients from Germany and Austria found no difference in outcomes between those treated with caplacizumab alone and those treated with plasma exchange. More recently, the Phase 3 MAYARI trial, a single-arm open-label study, reported that 93.5 percent of participants achieved remission without plasma exchange, with 97.8 percent achieving remission overall.

What makes this case particularly instructive is the mechanism. Caplacizumab binds to the A1 domain of von Willebrand factor but does not displace platelets that have already attached. It functions more as an anticoagulant than a thrombolytic — preventing new clots from forming rather than dissolving existing ones. Resolving established platelet-rich thrombi likely still requires ADAMTS13, which in conventional therapy is supplied through donor plasma. For patients with milder symptoms and presumably a smaller burden of existing microvascular thrombi, caplacizumab alone may suffice. That this patient, with severe neurological injury and profound anemia, recovered so rapidly suggests that even in advanced disease, blocking new thrombus formation can buy the body enough time to clear existing clots and regenerate damaged tissue — without a single unit of plasma.

The authors emphasize that earlier initiation of caplacizumab might have prevented the most dangerous phase of this patient’s illness, as TTP is fundamentally a time-dependent disease in which every hour of untreated microvascular thrombosis translates into additional organ damage. Current guidelines from the International Society on Thrombosis and Haemostasis recommend starting caplacizumab as early as possible once the diagnosis is confirmed. For patients who cannot or will not undergo plasma exchange — whether for religious convictions, hemodynamic instability, or logistical barriers — this case offers compelling evidence that a targeted antibody strategy, layered with escalating immunosuppression, can achieve complete recovery even in the face of life-threatening disease.

Subject of Research: Treatment of severe immune-mediated thrombotic thrombocytopenic purpura with caplacizumab without plasma exchange

Article Title: Case report: Caplacizumab without plasma exchange for severe thrombotic thrombocytopenic purpura

Article References: Hayes, S. M., Pease, D. F., Wiese, C. M., & Mazepa, M. (2026). Case report: Caplacizumab without plasma exchange for severe thrombotic thrombocytopenic purpura. Frontiers in Drug Delivery, 6, Article 1894135. https://doi.org/10.3389/fddev.2026.1894135

Image Credits: AI Generated

DOI: 10.3389/fddev.2026.1894135

Keywords: caplacizumab, thrombotic thrombocytopenic purpura, plasma exchange, ADAMTS13, von Willebrand factor, rituximab, cyclophosphamide, Jehovah's Witness, microangiopathic hemolytic anemia, immunosuppression, case report, hematology

The patient’s ordeal began in April 2026, when she was referred to her general practitioner with back pain radiating down her right leg. She received a five-day course of intramuscular corticosteroids, a muscle relaxant, and the anti-inflammatory drug diclofenac. The treatment brought only slight relief, but something far more alarming appeared: extensive hematomas bloomed at every injection site. That unexpected bleeding prompted laboratory tests, and the results were grim. Her hemoglobin had crashed to 66 grams per liter, a level consistent with severe anemia, and her platelet count had fallen to 107 billion per liter, well below the normal range. Elevated bilirubin hinted that red blood cells were being destroyed somewhere inside her circulation.

By the time she was admitted to the hematology clinic the following day, the picture had crystallized into something hematologists recognize instantly and fear deeply. Her blood smear showed schistocytes, fragmented red cells sheared apart as they squeezed through obstructed microvessels, making up a staggering 30 percent of her red cell population. Lactate dehydrogenase, a marker of cell destruction, was massively elevated at 1744 units per liter. Haptoglobin, a protein that mops up free hemoglobin, was undetectable. The Coombs test was negative, ruling out autoimmune destruction. Her platelet count kept falling, dropping to 29 billion per liter within days. Everything pointed to thrombotic microangiopathy, a family of disorders in which tiny blood clots shred red cells and consume platelets throughout the body.

The leading suspect was thrombotic thrombocytopenic purpura, or TTP, a fulminant condition caused by severe deficiency of the ADAMTS13 enzyme, which normally cleaves ultra-large von Willebrand factor in the blood. The patient’s PLASMIC score, a validated prediction tool, came back at 6, indicating a high probability of TTP. Following standard practice, clinicians did not wait for the enzyme result. Plasma exchange, the lifesaving mainstay of TTP treatment, was started immediately alongside corticosteroids. But the therapy failed. Her clinical condition and laboratory parameters showed no improvement, and when ADAMTS13 activity finally returned it was completely normal at 108.4 percent. TTP was excluded, the plasma exchange was stopped, and the diagnostic search pivoted toward a far more sinister possibility: a secondary microangiopathic hemolytic anemia driven by an underlying malignancy.

Cancer-related microangiopathic hemolytic anemia, abbreviated CR-MAHA, was first described by Brain and colleagues in 1970, who distinguished it from other thrombotic microangiopathies by its association with disseminated cancer, particularly mucin-producing tumors of the stomach, breast, and lung. The proposed mechanism was grimly elegant: tumor emboli lodging in the microvasculature and in-situ thrombosis mechanically fragmenting erythrocytes as they traverse the damaged vessels. The syndrome remains rare, documented mainly in individual case reports and small series, but the largest systematic review, encompassing 168 cases, found that adenocarcinomas dominate the list of culprits. Gastric carcinoma led at 26.2 percent, followed by breast, prostate, and lung cancers. More than 90 percent of patients had metastatic disease, and bone marrow infiltration was documented in over 80 percent of assessed cases.

The clues in this patient’s blood work soon multiplied. Tumor markers came back dramatically elevated: carcinoembryonic antigen at 101.7 micrograms per liter and carbohydrate antigen 72-4 exceeding 500 units per milliliter, roughly seventy times the upper reference limit. A re-review of her spinal MRI revealed multiple metastatic deposits throughout every visualized vertebra and her pelvic bones. Computed tomography of the chest, abdomen, and pelvis showed bilateral adrenal enlargement and abdominal lymphadenopathy with nodes up to 25 millimeters across. Gastric biopsies, taken through an endoscope that revealed macroscopically normal mucosa, showed only chronic gastritis, a deceptive finding given what lay beneath. The decisive evidence came from the bone marrow itself.

Bone marrow aspiration revealed clusters of metastatic cells, several times the size of a neutrophil, with eccentric nuclei occupying about three-quarters of the cell volume and abundant pale cytoplasm. The trephine biopsy showed near-complete replacement of normal hematopoietic tissue by metastatic adenocarcinoma composed of discohesive cells stuffed with intracytoplasmic mucin that pushed their nuclei to the periphery, producing the classic signet-ring appearance that gives this tumor its name. Immunohistochemistry sealed the diagnosis: the cells expressed CK7, CK20, CDX2, MUC1, MUC2, and MUC5, while GATA3 was negative. This immunophenotypic profile, combined with the soaring CA 72-4 level, pointed squarely to a gastrointestinal primary, most consistent with metastatic gastric signet-ring-cell adenocarcinoma. Colonoscopy could not be performed because of her poor condition. Referred to oncology, she could not receive cancer-directed treatment because of persistent severe thrombocytopenia. She died six days later.

Why does this particular cancer trigger such catastrophic blood destruction? The answer appears to lie in mucins, the sugar-decorated glycoproteins that signet-ring-cell carcinomas manufacture in abundance. Mucins can bind P-selectin on platelets and L-selectin on leukocytes, promoting the formation of platelet-leukocyte aggregates that seed microvascular thrombosis, sometimes without conventional thrombin generation. The same interaction underlies Trousseau syndrome, the migratory thrombophlebitis that has haunted cancer patients since the nineteenth century. Many of these tumors also express tissue factor, releasing procoagulant microvesicles that generate thrombin and deposit fibrin diffusely, blurring the line with disseminated intravascular coagulation. Loss of E-cadherin, a hallmark of diffuse-type gastric cancer, facilitates the early peritoneal and bone marrow dissemination characteristic of signet-ring-cell tumors, whose thin-walled, highly permeable sinusoids may create microenvironments especially vulnerable to erythrocyte fragmentation.

The case carries a practical message for clinicians everywhere: when microangiopathic hemolysis fails to respond to plasma exchange and ADAMTS13 activity is normal, the workup must not stop. Tumor-marker assessment, cross-sectional imaging, and, crucially, bone marrow examination should follow promptly, particularly when unexplained cytopenias or a leucoerythroblastic blood picture suggest marrow involvement. In this patient, bone marrow aspiration provided the first direct evidence of metastatic carcinoma and substantially accelerated the diagnosis before histopathological confirmation. Distinguishing CR-MAHA from TTP and DIC matters enormously, because fibrinogen, coagulation times, D-dimer levels, and the response to plasma exchange all differ across these entities, and the treatments are fundamentally incompatible. Plasma exchange, a cornerstone of TTP therapy, offers no sustained benefit in CR-MAHA when the underlying malignancy remains untreated.

The story is ultimately a tragic one, but it is also a scientific one. It demonstrates how a single blood smear, read carefully, can expose an entire hidden pathology, and how the peculiar biology of a mucin-producing tumor can announce itself through the destruction of red blood cells rather than through pain, weight loss, or any symptom a patient might recognize. For a woman with back pain and no prior medical history, the interval from first symptom to fatal diagnosis was measured in weeks. The clinicians who reported her case hope that by documenting the diagnostic pathway, the laboratory red flags, and the pitfalls of anchoring on TTP, they can help the next patient reach a diagnosis early enough for cancer-directed therapy to begin while there is still time for it to matter.

Subject of Research: Cancer-related microangiopathic hemolytic anemia revealing occult metastatic gastrointestinal signet-ring-cell carcinoma

Article Title: Cancer‐Related Microangiopathic Haemolytic Anemia Revealing Occult Metastatic Gastrointestinal Signet‐Ring Cell Carcinoma: A Clinicopathological Case Report and Practical Differential Diagnostic Approach

Article References: Jovanovic, D., Sretenovic, S., Jovanovic, D., Ilic, M., & Djurdjevic, P. (2026). Cancer‐Related Microangiopathic Haemolytic Anemia Revealing Occult Metastatic Gastrointestinal Signet‐Ring Cell Carcinoma: A Clinicopathological Case Report and Practical Differential Diagnostic Approach. Clinical Case Reports, 14(10), Article e73675. https://doi.org/10.1002/ccr3.73675

Image Credits: AI Generated

DOI: 10.1002/ccr3.73675

Keywords: microangiopathic hemolytic anemia, signet-ring-cell carcinoma, gastric cancer, thrombotic thrombocytopenic purpura, ADAMTS13, bone marrow metastasis, mucin, tumor markers, disseminated intravascular coagulation, plasma exchange, schistocytes, case report