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Thrombosis with Thrombocytopenia Syndrome (also termed Vaccine-induced Thrombotic Thrombocytopenia)

(Version 1.6; last updated August 12, 2021)

Input from James B. Bussel, MD; Jean M. Connors, MD; Douglas B. Cines, MD; Cynthia E. Dunbar, MD; Laura C. Michaelis, MD; Lisa Baumann Kreuziger, MD; Agnes Y. Y. Lee, MD, MSc; and Ingrid Pabinger-Fasching, MD.

Key Takeaways
Thrombosis with Thrombocytopenia Syndrome (TTS)

  • Definitive Diagnosis (must meet all five criteria):
  1. COVID vaccine 4 to 42 days prior to symptom onset# 
  2. Any venous or arterial thrombosis (often cerebral or abdominal)
  3. Thrombocytopenia (platelet count < 150 x 109/L)*
  4. Positive PF4 “HIT” (heparin-induced thrombocytopenia) ELISA
  5. Markedly elevated D-dimer (> 4 times upper limit of normal) 
     
  • Incidence is extremely low. Risk of death and serious outcomes of COVID-19, including thrombosis, far outweigh risk of TTS possibly associated with highly efficacious vaccines.
  • Urgent medical evaluation for TTS is indicated if any of the following develop 4 to 42 days after vaccination:
  • Severe headache
  • Visual changes
  • Abdominal pain
  • Nausea and vomiting
  • Back pain
  • Shortness of breath
  • Leg pain or swelling
  • Petechiae, easy bruising, or bleeding
  • If TTS is suspected, perform immediate CBC with platelet count and imaging for thrombosis based on symptoms.
  • If thrombocytopenia or thrombosis are present, recommend urgent consultation from hematologist with expertise in hemostasis. Avoid use of heparin until TTS has been ruled out or until an alternative other plausible diagnosis has been made.
  • Initial work-up (a normal platelet count is less concerning for TTS*):
  • CBC with platelet count and peripheral smear
  • Imaging for thrombosis based on signs/symptoms
  • PF4-ELISA (HIT assay); draw blood prior to any therapies
  • Fibrinogen and D-dimer
  • Initiate therapy with intravenous immunoglobin and nonheparin anticoagulation pending PF4 ELISA results if:
  • Confirmed thrombosis AND at least one of the following
    • Low platelets* OR
    • Markedly elevated D-dimer OR
    • Both
       

If PF4 ELISA returns negative and there is no thrombocytopenia, TTS is ruled out; treat as standard venous thromboembolism.

OR

  • If thrombocytopenia and very high D-Dimer in absence of known thrombosis, particularly in the presence of severe headache, check PF4 ELISA, and consider treatment (see Q2)
  • If thrombocytopenia but no thrombosis and negative PF4 ELISA: likely ITP (see Q4)
  • Avoid platelet transfusions unless other treatments have been initiated AND life-threatening bleeding or imminent surgery  
  • Consider referral to tertiary care center if TTS is confirmed.

Knowledge about TTS continues to evolve, and updates will be made as new data become available.

#To date, TTS appears far more likely following AstraZeneca/Johnson and Johnson adenoviral vaccines than Moderna/Pfizer mRNA vaccines..

*A patient who presents with thrombosis and a normal platelet count post-vaccination might be in an early stage of TTS. Continued assessment for development of thrombocytopenia/TTS is required. Use of a non-heparin anticoagulant may be indicated if patient is 4 to 42 days post–vaccine with all other facets of the syndrome pending PF4 ELISA testing and additional CBCs.

On April 13, the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) suggested pausing administration of the AD26.COV2.S Johnson & Johnson (JJ) vaccine to allow investigation of several cases of severe thrombosis with thrombocytopenia occurring post-vaccination. This announcement came on the heels of the initial reports of similar events in individuals receiving the CHaDOx1 nCov-19 AstraZeneca (AZ) vaccine outside the United States. Comprehensive clinical and laboratory characteristics of TTS have been reported in retrospective series and a large prospective cohort.  This syndrome has been termed “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” or “vaccine-induced immune thrombotic thrombocytopenia (VITT)” but has been termed “thrombosis with thrombocytopenia syndrome (TTS)” by the CDC and FDA. A single case of what appears to be the same syndrome has now been published following the Moderna mRNA vaccine; however, the risk appears far lower for the two mRNA vaccines.

Following FDA/CDC review of all sources of vaccine event reporting in the United States following JJ vaccine administration, and a detailed risk/benefit analysis, the CDC Advisory Committee on Immunization Practices recommended that the JJ vaccine be available in the United States for persons aged 18 years and older. The overall safety and efficacy of the JJ vaccine compared to the risk of mortality from COVID-19 disease was thought to far outweigh the very low risk of TTS. The updated incidence as of the CDC review was two per million for the JJ vaccine, based on a total of 15 cases reported following 7.98 million doses administered. The most recent information from the United Kingdom suggests an incidence for the AstraZeneca vaccine of 20.3 per million doses in those aged 18 to 49 years compared to 10.9 per million doses in those aged 50 years and older.

COVID-19 has a substantial risk of serious outcomes including thrombosis and death. Based on current information, we strongly agree that the risks of COVID-19 disease far outweigh the risk of very rare side effects such as TTS associated with the highly efficacious SARS-CoV-2 vaccines. Of note, there is no information to date on any increased risk for TTS in patients with blood diseases and/or pre-existing risk factors for thrombosis or autoimmunity. The single-dose JJ vaccine may be particularly attractive for administration to patients before initiation of chemotherapy or other immunosuppressive interventions, even if eventually boosters are suggested.

This FAQ is designed to provide an overview of considerations around the diagnosis and treatment of TTS. Specialists with expertise in thrombosis should be consulted as soon as TTS is diagnosed or under consideration, and many institutions will devise algorithms based on local availability of laboratory testing and drug availability.

What is thrombocytopenia with thrombosis syndrome (TTS)? 

A syndrome characterized by venous or arterial thrombosis, particularly at unusual sites including cerebral sinus venous thrombosis (CSVT)/splanchnic thrombosis; mild to severe thrombocytopenia; and positive PF4-heparin ELISA (“HIT” ELISA) was first described following the ChAdOx1 nCov-19 AZ vaccine, utilized extensively in the United Kingdom, Europe, and Canada, but not yet available in the United States. The largest and most recent series of 220 definite and 50 probable cases from the UK showed a median age of 48, and no gender bias.  Few patients had other known risk factors for thrombosis. Many of the patients were critically ill by the time thrombosis and thrombocytopenia were discovered, and up to one-third of the initially reported patients died.  The presence of severe thrombocytopenia (<30,000/uL) and/or intracranial hemorrhage was associated with the highest mortality.

TTS has also been reported in patients following the Ad26.COV2.S JJ vaccine. The clinical syndrome and time post-vaccination are very similar to cases following the AZ vaccine. Both vaccines utilize recombinant adenoviral vectors (chimpanzee for AZ and human for JJ) encoding the SARS-CoV-2 spike protein immunogen. In June 2021, a report of a single patient receiving the Moderna mRNA vaccine was published documenting a full-blown TTS syndrome. The UK regulatory agency has reported 15 and two cases of major thrombosis with concurrent thrombocytopenia with Pfizer and Moderna vaccines, respectively; whether these are cases of TTS has not been confirmed.

The striking clinical similarities of TTS to heparin-induced thrombocytopenia (HIT) and the uniformly positive PF4-heparin ELISAs in these index cases led investigators to identify circulating PF4-reactive antibodies able to activate platelets in the absence of heparin. Intravenous immunoglobulin (IVIG) or a monoclonal antibody blocking the Fc receptor were able to prevent platelet activation by these antibodies in vitro. These clinical and laboratory features are similar to rare cases of HIT-like autoimmune thrombosis with thrombocytopenia, previously described following surgery, certain medications or infections in patients not receiving heparin. 

What clinical presentation should trigger consideration of TTS, and what is an appropriate initial work-up?

Mild-to-moderate constitutional symptoms such as fever, fatigue, headache, or muscle aches are common in the first 24 to 48 hours following vaccination and are not suggestive of TTS. Patients with severe, recurrent, or persistent symptoms from 4 to 42 days following COVID-19 vaccination, including intense headache, abdominal pain, back pain, nausea and vomiting, vision changes, change in mental status, shortness of breath, leg pain and swelling, and/or bleeding/petechiae, should be evaluated urgently by a medical provider, and consideration given to underlying TTS. The peak time period for initial symptoms is days 6 to 14. 

Diagnostic criteria of TTS/VITT vary between reports and based on geography. The five criteria for “Definitive” TSS/VITT (1. COVID vaccine 4 to 42 days prior to symptom onset; 2. Any venous or arterial thrombosis; 3. Thrombocytopenia [platelet count < 150 × 109/L]; 4. Positive PF4 “HIT” [heparin-induced thrombocytopenia] ELISA; 5. Markedly elevated D-dimer [> 4000 FEU or equivalent]) may not be met by every patient on presentation.  As further data are gathered on patients with possible TTS, “grey zone” probable or possible TTS/VITT should be considered in patients with any concerning symptoms in the post-vaccine time period. There are no clear answers, and as data on patients with earlier TTS diagnosis become available, recommendations may change. Examples of such situations include:

  • Patients followed by hematologists/oncologists who present post-vaccination with other potential reasons for thrombocytopenia and thrombosis. The PF4 ELISA can assist with diagnosis of TTS in these patients if thrombocytopenia is worsened from baseline.
  • Patients may present with a typical lower extremity venous thromboembolism (VTE) following vaccination in the presence of mild thrombocytopenia or a single low normal value. At present, avoidance of heparins in patients presenting with VTE in the post-vaccine window is reasonable while awaiting PF4 ELISA and following the platelet count. 
  • Patients who have thrombocytopenia and markedly elevated D- without other clear cause, even in the absence of documented thrombosis or suggestive symptoms, might benefit from initiating treatment while waiting for PF4 ELISA results. In particular, IVIG might be beneficial in those with platelet counts below 20 × 109/L as this reflects a consumptive coagulopathy. A recent report documented rapid improvement in laboratory parameters in such a patient treated with both IVIG and a non-heparin anticoagulant, without progression to thrombosis. Patients with severe headache, even in the absence of detectable cerebral venous sinus thrombosis on imaging, have been reported to be at high risk if other criteria for TTS are met, and both IVIG and anticoagulation should be strongly considered to prevent further progression.
  • Patients with typical thrombosis, thrombocytopenia and very high D-dimers in the correct time window following vaccination, but a negative initial PF4 ELISA. This situation arose in 2.7 percent of the largest series and can be started on treatment for VITT (see below) while awaiting repeat PF4 ELISA and specialized platelet activation testing..

Initial work-up (note: draw blood prior to any therapeutic interventions such as IVIG, given potential interference with diagnostic assays):

  1. CBC with platelet count and peripheral smear. Median initial platelet count in largest series was 47,000/µL with a wide range.3 Smear is needed to rule out pseudothrombocytopenia from platelet clumping.
  2. Imaging for thrombosis based on symptoms, focused on detection of cerebral sinus venous thrombosis (CSVT) with CT or MRI venogram, splanchnic thrombosis, pulmonary emboli, and/or DVT.
  3. D-dimer: the majority of TTS patients have markedly elevated values, over four times upper limit of normal.
  4. Fibrinogen: some TTS patients are reported to have low values
  5. PF4-heparin ELISA: almost 100 percent of cases reported had positive assays, with optical density greater than 2.0 to 3.0 in the majority. Non-ELISA rapid immunoassays for HIT are not sensitive or specific for TTS and should not be used.

Patients with worrisome symptoms and/or positive imaging in addition to low platelet counts and high D-dimer can be considered to have TTS and should be started on treatment (see below) while awaiting PF4 ELISA results. Whether the degree of PF4 ELISA positivity correlates with risk of TTS is unknown. Patients with low fibrinogen and extremely high D-dimer, suggesting disseminated intravascular coagulation, fall within the TTS syndrome. Microangiopathy with red cell fragmentation and hemolysis has not been a common feature of reported cases; however, at least one case with both TTS and TTP/HUS features has been reported. Thus, review of a blood smear and attention to signs of intravascular hemolysis would be appropriate.

Patients with isolated thrombocytopenia and continued absence of thrombosis may have post-vaccine ITP and not TTS (see below), as confirmed by a negative PF4 ELISA.

How should TTS be treated? 

This is a newly described syndrome, and all recommendations are based on extrapolation from HIT and to non–heparin-dependent autoimmune thrombotic thrombocytopenias, analysis of the clinical features in reported cases, and predictions based on laboratory investigations of pathophysiology. Several groups have published detailed position papers on TTS that include expert consensus recommendations and algorithms. Note that prospective clinical treatment studies do not exist, and that the response rate of these interventions has not been established.

The risk of heparin administration remains unclear. Many patients presenting prior to the initial reports of TTS received heparin anticoagulation, with poor outcomes; however, these patients were clinically very advanced before TTS was recognized. The recent large UK series reported 20 percent mortality in those receiving heparin and 16 percent in those not receiving heparin. While the syndrome resembles HIT, current understanding of TTS pathophysiology suggests that VITT antibodies bind the same site on PF4 as heparin, which can explain the inhibition of platelet activation by heparin seen in some patients’ laboratory testing with VITT.  Given the availability of alternative anticoagulation regimens and lack of consensus regarding the safety of heparin in TTS, we currently suggest avoiding heparin or low molecular weight heparin (LMWH) anticoagulation in these patients.

In patients presenting with thrombocytopenia, documented or suspected thrombosis, and a positive or pending PF4 ELISA 4-42 days post-vaccination, we recommend rapid initiation of treatment, analogous to treatment of severe HIT, including:

  1. IVIG 1 g/kg daily for two days. Note that patients with new clots arising post-IVIG have been reported; thus, patients should be carefully monitored even after treatment has begun, and initiation of anticoagulation coincident with IVIG is recommended.
  2. Non-heparin anticoagulation, chosen based on the clinical status and organ function of the patient:
    1. Parenteral direct thrombin inhibitors (argatroban or bivalrudin), OR
    2. Direct oral anticoagulants without lead-in heparin phase, OR
    3. Fondaparinux, OR 
    4. Danaparoid
  3. Low fibrinogen or bleeding are associated with TTS and should not absolutely preclude anticoagulation, particularly if platelets are >20,000/μL or rising following IVIG initiation. Concurrent replacement of fibrinogen in patients with bleeding and/or very low values should be considered. 
  4. Based on similarities to HIT, avoid platelet transfusions. However, risk/benefit assessment in individual patients with serious bleeding and/or need for surgical intervention may favor platelet transfusion following initiation of IVIG, non-heparin anti-coagulation, and fibrinogen replacement (if deficient).
  5. Corticosteroids have been administered along with IVIG in some cases, with no consensus or data to date on their role.
  6. Avoid aspirin as either treatment or prophylaxis for TTS. Aspirin is not efficacious in preventing HIT antibodies from activating platelets and could increase the risk of bleeding.
  7. Additional therapies: Plasma exchange has been utilized in patients with severe disease. In the UK series, a survival of 90 percent was reported in patients treated with plasma exchange. It can be considered if a patient shows continued thrombosis despite IVIG and non-heparin anticoagulation. The large extravascular volume of distribution of IgG antibodies, causative in both HIT and TTS, prevents rapid or complete removal via plasma exchange, and the concurrent bleeding complications in TTS may make catheter placement and prolonged apheresis challenging. Complement inhibition with eculizumab has been utilized in several patients progressing after IVIG and anticoagulation, with evidence for improvement.

At this time, the duration of risk of thrombosis in patients with TTS is not known. Pending more data, those with documented thrombosis should receive a minimum of three months anticoagulation, as for any provoked VTE.

What if a patient presents with thrombocytopenia or bleeding post-vaccination?

Over 100 cases of new-onset acute immune thrombocytopenia purpura (ITP), with at least one fatal, have been diagnosed in the same timeframe following vaccination as TTS (median, 8 days). These occurrences have been noted following AZ and JJ as well as Moderna and Pfizer vaccines. The platelet count at presentation is often <10,000/μL, somewhat lower than in TTS (median, 20,000/μL), and thromboses have not been associated with these cases, although very few cases had a PF4 ELISA checked. Most presented with bleeding. Estimates to date suggest that post–COVID vaccine ITP is rare (1 in 100,000 to 1 in 1,000,000) and may be related to vaccination or represent a coincidental event. Most patients respond to the combination of IVIG, and/or steroids, with platelet transfusions if bleeding. Thrombopoietin agents and possibly a single dose of vincristine may be useful if there is not an immediate (2-4 days or cessation of bleeding) response to IVIG and/or steroids. Avoidance of rituximab is important because of slow onset of action (weeks), negation of recent vaccine-induced immunity, and inability to vaccinate again for more than six months. For more details regarding treatment see the ITP FAQ.

It is important to rule out TTS with a negative PF4 ELISA assay in patients presenting with thrombocytopenia four to 42 days post-vaccination, even in the absence of symptoms suggestive of thrombosis. While awaiting PF4 ELISA results, IVIG could be administered to patients with profound thrombocytopenia and bleeding, given the indication for this medication in the treatment of both ITP and TTS. 

Patients with pre-existing ITP or other causes of thrombocytopenia may have transient further lowering of platelet count following vaccination.  Whether a PF4 ELISA should be sent in such patients in the absence of signs of thrombosis is unclear, but until more information is available, it would seem prudent to send a screening ELISA in those with a clear significant decrease in platelet count occurring during the relevant timeframe.

Resources

Webinar: the diagnosis and management of TTS (VITT)

This seminar reviews the background, diagnosis, and clinical management of this emerging disorder with CDC and ASH experts.

View the Webinar

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