Moschcowitz syndrome

Pathophysiology

TTP is caused by a severe deficiency of ADAMTS13, a zinc metalloprotease that cleaves ultra-large von Willebrand factor (ULVWF) multimers. Deficiency permits spontaneous ULVWF-mediated platelet aggregation in the microvasculature, leading to widespread thrombi.

• Acquired TTP: >90% of adult cases; due to autoantibodies inhibiting ADAMTS13
• Congenital TTP (Upshaw–Schulman syndrome): rare autosomal recessive disorder due to mutations in the ADAMTS13 gene

Epidemiology

• Incidence: ~2–6 cases per million per year
• Median age: 30s–40s; congenital cases present earlier
• Gender: Female predominance (~2:1)
• Ethnicity: Higher prevalence in African and Hispanic populations
• Mortality: >90% untreated; <10–15% with prompt plasma exchange and immunosuppression

Clinical Presentation

While the classic “pentad” is infrequently complete, patients typically present with:

• Microangiopathic haemolytic anaemia (MAHA) – fatigue, pallor, jaundice; schistocytes on blood film
• Thrombocytopenia – petechiae, purpura, mucosal bleeding
• Neurologic symptoms – confusion, headache, seizures, stroke-like episodes
• Renal involvement – mild to moderate elevation in creatinine (less severe than HUS)
• Fever – not always present

Other potential manifestations:

• Cardiac: arrhythmias, elevated troponins
• Gastrointestinal: abdominal pain, pancreatitis
• Retinopathy: cotton-wool spots, retinal haemorrhages

Diagnosis

Diagnosis is often presumptive and treatment started emergently before ADAMTS13 results are available.

• Blood film: Schistocytes (fragmented RBCs)
• Labs: Elevated LDH, indirect hyperbilirubinaemia, low haptoglobin, reticulocytosis, thrombocytopenia
• Coagulation: Typically normal PT/aPTT (helps distinguish from DIC)
• ADAMTS13 activity:
  • <10% confirms diagnosis
  • Anti-ADAMTS13 antibodies confirm acquired TTP

Treatment

Acute Management

• Plasma exchange (PEX) – mainstay of therapy; removes autoantibodies and replenishes ADAMTS13
• Corticosteroids – immunosuppression for acquired disease
• Caplacizumab – anti-vWF nanobody; prevents platelet-vWF interaction; reduces time to platelet recovery and relapses
• Rituximab – anti-CD20 monoclonal antibody for refractory or relapsing disease
• Supportive care – transfusions for anaemia; platelet transfusion avoided unless life-threatening bleeding

Long-Term Management

• Monitor ADAMTS13 activity and antibody levels
• Evaluate for autoimmune comorbidities
• Education regarding relapse signs, especially in congenital cases

---

History

1924 – First clinical description by Eli Moschcowitz (1879–1964). Presented a case of a previously healthy 16-year-old girl with abrupt onset of petechiae, pallor, fever, and neurologic decline. Autopsy revealed widespread hyaline thrombi in terminal arterioles and capillaries. Described as: “An acute febrile pleiochromic anemia with hyalinethrombosis of the terminal arterioles and capillaries.”

Emanuel Libman (1872–1946) – Mentor to Moschcowitz and influential early 20th-century pathologist who supported the initial case report and its interpretation.

1936 – Baehr, Klemperer, and Schiffrin delineate clinical-morphologic features. Expanded the concept as a discrete syndrome distinct from other purpuras. Introduced differential features and proposed “platelet thrombosis syndrome” as an alternate term.

1966 – Amorosi and Ultmann propose TTP clinical pentad. Codified five features: MAHA, thrombocytopenia, neurologic symptoms, renal dysfunction, and fever.
Reference: Amorosi EL, Ultmann JE. Medicine (Baltimore). 1966;45(2):139–59

1970s – Plasma exchange emerges as lifesaving therapy. Empirical use of plasma exchange shown to drastically reduce mortality.
Reference: Canadian Apheresis Study Group, 1991

1982 – Moake et al. identify ULVWF in TTP. Discovery of unusually large vWF multimers in TTP patients’ plasma; postulated impaired degradation due to absence of “depolymerase”.
Reference: Moake JL et al., NEJM, 1982

1996–1998 – ADAMTS13 identified as VWF-cleaving protease. Independently discovered by Furlan and Tsai; subsequent studies link severe ADAMTS13 deficiency with TTP.
Reference: Furlan M, Tsai HM et al., 1997–1998

2001 – Inherited TTP (Upshaw–Schulman syndrome) linked to ADAMTS13 mutations

Described in patients with congenital absence of ADAMTS13 activity.
Reference: Levy GG et al., Nature, 2001

---

Associated Persons

• Eli Moschcowitz (1879-1964) American clinician and pathologist; first described the syndrome bearing his name
• George Baehr, Paul Klemperer, Arthur Schiffrin – Defined clinical features distinguishing TTP from other purpuras (1936)
• Edward L. Amorosi and John E. Ultmann – Introduced diagnostic pentad in 1966
• James N. George – Major figure in modern TTP diagnosis and registry development
• Josef Moake – Identified ULVWF multimers in TTP
• Furlan and Tsai – Independently discovered ADAMTS13 and its role in TTP pathophysiology
  
  
• Emanuel Libman (1872-1946)

---

Alternative names

• Thrombotic thrombocytopenic purpura,
• Thrombotic thrombocytopaenic purpura
• TTP

---

References

Original articles

• Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries. A hitherto undescribed disease. Proceedings of the New York Pathological Society, 1924; 24: 21-24
• Moschcowitz E. An acute febrile pleiochromic anemia with hyalinethrombosis of the terminal arterioles and capillaries: An undescribed disease. Archives of internal medicine 1925; 36(1): 89–93

Modern interpretation

• Marcus AJ. Moschcowitz Revisited. N Engl J Med. 1982 Dec 2;307(23):1447-8.
• Asada Y, Sumiyoshi A, Hayashi T, Suzumiya J, Kaketani K.Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen.Thromb Res 1985; 38: 469–79.
• Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinctpathologic entities. A review of 56 autopsy cases. Arch Pathol LabMed 2003; 127: 834–9
• Lämmle B, Kremer Hovinga JA, Alberio L. Thrombotic thrombocytopenic purpura. J Thromb Haemost. 2005 Aug;3(8):1663-75.
• Nickson C. Thrombotic thrombocytopenic purpura. CCC