Michael B. Streiff, MD

Medical Director

The Johns Hopkins Anticoagulation Management Service and Hemostatic Disorder 

Stewardship Program

The Johns Hopkins Special Coagulation Laboratory

Professor of Medicine & Professor of Pathology

Johns Hopkins University School of Medicine

Pathogenesis and Management of Thrombosis with 

Thrombocytopenia Syndrome (TTS)

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Disclosures: Michael B. Streiff, MD

• Consulting

•Bristol-Myers Squibb

• Coagulo Medical Technologies

•Dispersol

•Janssen

• Pfizer

•Research support

•AHRQ

•Janssen

•NIH/NHLBI 

• PCORI
What is Cerebral Venous Sinus Thrombosis?

Clinical characteristics: Thrombosis in the deep or 

superficial veins of the brain 

Incidence: 10-15 cases per million 

Mean Age: 35 years

Gender distribution F:M 2.2 : 1

Clinical presentation: Headache, seizures, limb 

weakness, reduced consciousness/coma

Risk factors: Oral contraceptives, clotting disorders, 

pregnancy, cancer, infections, surgery

Diagnosis: Contrast CT or MR venogram

Treatment: Anticoagulation, thrombolysis

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Capecchi M, Abbattista M, Martinelli I. J Thromb Haemost. 2018 Oct;16(10):1918-1931. Stam J. N Engl J Med. 2005 Apr 28;352(17):1791-8.
What are the clinical characteristics of TTS?

Associated with replication-defective adenoviral vector SARS-CoV-2 vaccines 

Incidence: Estimated 1 case per 100,000-250,000/vaccine recipients 

Age range: 21- 77 years (90% less than 60)

Gender distribution F:M 2.5 : 1

Median onset: 10 days (range 5-24 days)

Thrombotic events: Cerebral venous sinus thrombosis (N=27), DVT/PE (10), Abdominal vein clots (7), Arterial 

clots (6)

Heparin induced thrombocytopenia testing: Platelet factor 4 antibody immunoassay positive, Platelet 

activation assays (variable) 

Platelet nadir: 27,000/μL (range 7-113,000) , Fibrinogen nadir: 125 mg/dL (range 40-568), D dimer ↑↑↑

Progression of thrombosis on heparin, platelet recovery with IVIG 

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Greinacher A, et al. N Engl J Med. 2021 Apr 9. PMID: 33835769. Schultz NH, et al. N Engl J Med. 2021 Apr 9. PMID: 33835768. Scully M, et al. N Engl J Med. 2021 Apr 16. PMID: 33861525.
Comparison of thrombotic events after Oxford-AZ 

and Johnson + Johnson SARS-CoV-2 vaccines

Oxford-AZ SARS-CoV-2 Vaccine Cases

• Median age 40 (range 21-77)

• Gender: F:M 2.5:1

• Onset: 5-24 days after vaccine

• Symptoms: Headache, backache, abdominal 

pain, visual disturbance, leg/arm weakness

• Thrombosis: Cerebral , Abdominal veins, 

DVT/PE, arterial thrombosis

• Platelet nadir: 7-113,000

• Heparin-Platelet factor 4 immunoassaypositive 

• Platelet activation assay- positive 

Johnson + Johnson SARS-CoV-2 Vaccine cases

• Age range teens to 50s

• Gender F:M 8:0

• Onset: 6-13 days

• Symptoms: Headache, lethargy, back pain, 

abdominal pain, neurologic symptoms

• Thrombosis: Cerebral veins, abdominal 

veins

• Platelet nadir: 10-127,000 

• Heparin-Platelet factor 4 immunoassay- positive 

• Platelet activation assay-negative 4 of 5

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Greinacher A, et al. N Engl J Med. 2021 Apr 9. PMID: 33835769. Schultz NH, et al. N Engl J Med. 2021 Apr 9. PMID: 33835768. Scully M, et al. N Engl J Med. 2021 Apr 16. PMID: 33861525.
Pathogenesis of TTS Appears to be Similar to Autoimmune 

Heparin Induced Thrombocytopenia

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Hogan M, Berger JS. Vasc Med. 2020 Apr;25(2):160-173. 

Pathogenesis of

Heparin-induced 

thrombocytopenia
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Heparin Induced Thrombocytopenia Antibodies Lead to 

Multicellular Activation of Coagulation

Marchetti M, Zermatten MG, Bertaggia Calderara D, Aliotta A, Alberio L. J Clin Med. 2021 Feb 10;10(4):683.
TTS is similar to Autoimmune Heparin Induced 

Thrombocytopenia 

• Laboratory testing consistent with autoimmune heparin induced 

thrombocytopenia

• Positive platelet factor 4 immunoassay and platelet activation assays

• Platelet activation enhanced by addition of platelet factor 4

• Platelet activation inhibited by high concentrations of heparin

• Platelet activation blocked by intravenous immunoglobulin

• Clinical course consistent with heparin induced thrombocytopenia

• Onset mirrors onset of autoimmune thrombocytopenia

• Thrombosis and thrombocytopenia worsens with heparin treatment

• Clinical manifestations improve with non-heparin anticoagulation and IVIG

• Etiology of Thrombotic Thrombocytopenia Syndrome is Unclear

• Does not appear to molecular mimicry between platelet factor 4 and SARS-CoV2 spike protein

• 0 of 222 patients with SARS-CoV-2 infection have platelet activating antibodies 

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Greinacher A, et al. N Engl J Med. 2021 Apr 9. PMID: 33835769. Geinacher A et al. Research Square April 16 2021
Management of Thrombosis Thrombocytopenia 

Syndrome

• Maintain a high index of suspicion for any patient that presents with symptoms of 

a clot in association with thrombocytopenia after recent (within 3 weeks) 

administration of the J+J SARS CoV2 vaccine

• Confirm the thrombotic event

• Send testing for heparin-induced thrombocytopenia with platelet factor 4 

immunoassay and platelet activation assay

• Consult a hematologist to confirm the diagnosis and rule out other diagnostic 

possibilities

• Treat clots with a non-heparin anticoagulant

• Treat the thrombocytopenia with intravenous immunoglobulin

• Avoid platelet transfusions

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American Society of Hematology COVID-19 Resources at https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia
Questions

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