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Write-up: a 27 y.o. female with a history of Covid infection December 26, 2020, positive covid test December 29, 2020. She had approximately 2 weeks of symptoms including generalized body ache and generalized weakness. Fatigue and some headache. Had some persistence of symptoms after that time. Had some benefit from ibuprofen. Was seen at emergency room on January 27, 2021 stating that she felt that all her symptoms of Covid had resolved except for some chest pain which awoke her on January 27. She presented to the emergency room. Had sinus tachycardia at 113 but otherwise unremarkable physical exam, laboratory studies with white blood count elevated 16,004-20, hemoglobin 13.7 g hematocrit 41.8%, MCV 87.1, RDW 12.7%, platelet count 329,000, segs 72.8%, lymphs 20.6%, monocytes 4%, eosinophils 1%, basophil 0.6%. BUN 10.1, creatinine 0.8, AST 24, ALT elevated 56, alkaline phosphatase 68, total protein 7.6, total bilirubin 0.3, albumin 3.6, globulin by subtraction 4.0, troponin less than 0.02, D-dimer quantitative 0.22, urine pregnancy test normal. Chest x-ray normal. Chest pain appears to be musculoskeletal and was reproduced by palpation of her chest wall. No evidence of deep venous thrombosis or pulmonary embolism. D-dimer was normal. Heart rate returned to normal after some intravenous fluids. Patient discharged on Zithromax 500 mg day 1 and then to 50 mg days 2 through 5. Also continued on ibuprofen. Received Johnson and Johnson vaccine April 5, 2021. Over the next week patient started having increasing soreness. Her joints hurt more than usual and her headache was worse. She had a sensation that her legs were "numb and tingly" starting at her buttocks and extending down her leg. Because of reported incidence of cerebral sinus thrombosis or cerebral vein thrombosis patient appropriately presented for screening in the emergency room and was sent for appropriate imaging. April 16, 2021 CT scan of head with and without contrast no acute intracranial hemorrhage, no mass-effect or midline shift. On contrast-enhanced images there appears to be a lobular nonocclusive filling defect in the far lateral right transverse sinus. Lobular occlusive filling defect is also likely present in the mid to central right transverse sinus. Short segment filling defect in the medial left transverse sinus. Remainder of sinuses and internal cerebral veins are patent. Focal lobular filling defect within the confluence of the right and transverse sinus most likely related to arachnoid granulation. No edema hemorrhage of the cerebellum or cerebrum. No other significant findings. April 16, 2021 confirmatory MRI angiogram of head without contrast with no restricted diffusion to suggest acute or subacute infarct. Contrast void in the middle to central right transverse sinus consistent with occlusive thrombus. Nonocclusive thrombus in the far lateral right transverse thrombus. Narrowing of the medial left transverse sinus without complete occlusion. April 16, 2021 2345 hrs. inital hematology consultation. D-dimer and fibrinogen levels have been requested stat and are still pending. If fibrinogen level is low will replace with cryoprecipitate. If D-dimer is elevated barely confirms diagnosis of possible vaccine related thrombosis. The fact the patient is not thrombocytopenic at this time is encouraging, however despite the lack of thrombocytopenia she still has clearly documented symptomatic nonocclusive and occlusive thrombus in her cerebral sinus. From UPtoDate.com Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine) ? On April 13, 2021, the US Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) recommended pausing administration of AD26.COV2.S to further investigate rare cases of cerebral venous sinus thrombosis and thrombocytopenia . As of that date, six cases had been reported, all in females aged 18 to 48 years with onset 6 to 13 days after vaccination; during this period, 6.8 million doses were administered (with 1.5 million doses in females of that age range) [121-123]. Since some vaccine recipients have not been followed for longer than the time frame over which these symptoms develop, the incidence may change with additional follow-up. Initial symptoms included headache, backache, chills, and fatigue, and progressed to focal neurologic deficits. Intracerebral hemorrhage and thromboses at other sites were also seen in some patients. All of the five patients who were tested for the anti-PF4 HIT antibody tested positive. Another case, in a young male who was a vaccine recipient in one of the pre-emergency use authorization efficacy trials, had been previously reported. These cases appear similar to those reported following ChAdOx1 nCoV-19/AZD1222, another adenovirus-vector vaccine. Although rare, the observed number of events exceeded the expected rate among females <50 years old. Given the extreme rarity of these events, the FDA and CDC acknowledge that they recommended the pause out of an abundance of caution and to ensure awareness of these rare events. ?Evaluation and management of possible thrombotic complications ? Recipients should be aware of the possible association and seek immediate care for signs and symptoms suggestive of thrombocytopenia (eg, new petechiae or bruising) or thrombotic complications (including shortness of breath, chest pain, lower extremity edema, persistent severe abdominal pain, unabating severe headache, severe backache, new focal neurologic symptoms, and seizures) . In such cases, some experts suggest evaluation with complete blood count and differential (including the platelet count), quantitative D-dimer, HIT testing, and imaging of any suspected site of thrombosis [113,114,125]. Onset 4 to 20 days after vaccination, platelet count <150,000/microL, elevated D-dimer, and a positive anti-PF4 antibody (HIT antibody) suggest the diagnosis. Treatment with a non-heparin/non-warfarin anticoagulant (eg, argatroban or direct oral anticoagulant) and intravenous immune globulin has been suggested. The CDC recommends not using heparin in individuals with thromboses following receipt of Ad26.COV2.S unless HIT testing is negative . (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis" and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on ''Terminology and HIT variants'' and "Management of heparin-induced thrombocytopenia", section on ''Role of IVIG''.) As stated above all the 6 cases were "all in females aged 18 to 48 years with onset 6 to 13 days after vaccination" this would certainly fit the timeframe that we are seeing in this case. Recommendations from national guidelines would be to start treatment with dexamethasone immediately while awaiting intravenous gammaglobulin. To pursue intravenous gammaglobulin treatment at 1 g/kg over 1 to 2 days. It is recommended to avoid heparin and instead use direct factor X inhibitor such as Eliquis, which this patient is already been started on. There is unfortunately considerable risk that even though patient''s symptoms appear mild at this time, that she may deteriorate in the very near future and I would recommend treating her aggressively at this time with dexamethasone and intravenous gammaglobulin while we are awaiting further testing. Patient clearly has had unusual thrombosis, especially in a 27-year-old. With the fact that she had headache dating back to January, it is impossible to determine the acute versus chronic nature of her venous sinus thrombosis. Covid infection does cause increase in coagulation as well. However, given the small risk of tragic outcome with cerebral vein and sinus thrombosis in the setting of Covid vaccinations, we will proceed aggressively with treatment starting tonight with intravenous gammaglobulin and intravenous dexamethasone. Will require rapid fasting glucoses to evaluate possible hyperglycemia from high-dose dexamethasone. Will consider stopping dexamethasone at 48 hours. Current recommendation for gammaglobulin would be single 1 g/kg or 500 mg/kg over 2 days. No recommendations for treatment beyond this point. Current recommendations for gammaglobulin dosing would recommend using an adjusted dose for patients with greater than 125% of their ideal body weight. This patient at 122 kg on a 5 foot 2 inch frame does qualify for adjusted dose and her orders reflect that. I appreciate the opportunity see this patient this evening and consultation requested by Dr. We will follow patient in hospital. Hopefully she will have gradual improvement and avoid any serious or tragic complications of her cerebral sinus thrombosis. We will have pharmacy report possible adverse reaction to Johnson & Johnson vaccine to the FDA as required by law. April 17, 2021 follow up. No new events. Laboratory studies remained excellent. White blood count is further elevated, however, this may be secondary to high-dose dexamethasone with a white blood count of 16,060. Hemoglobin 14.0 g hematocrit 42.8%, MCV 86.8, RDW 12.9%. Platelet count is actually increased slightly at 374 as of 9:10 AM this morning. Differential shows left shift as expected with dexamethasone. Results from yesterday showed fibrinogen normal at 369 (180?415) pro time normal at 10.4 seconds with INR of 0.97, PTT 26.7. D-dimer 0.23 (0.19?0.50). With platelet count, fibrinogen and D-dimer normal I am inclined to believe that this is not an acute post vaccination HIT-like phenomena. If it were I would still expect to see some degree of thrombocytopenia elevated D-dimer and perhaps low fibrinogen. The other explanations for her cerebral venous sinus thrombosis are either idiopathic spontaneous and merely coincidentally associated at the exact same time as her Covid infection or more likely, cerebral venous sinus thrombosis secondary to hypercoagulable state secondary to her Covid infection from December 2020. Unfortunatly there is no way to accurately date the acuity of the venous thrombosis in her cerebral sinus. HIT Testing is still pending and most likely will not be available for 3-4 more days despite being ordered stat. Have called the laboratory and asked them to check with our outside reference lab what the expected return time is on this test. (LabCorp says "Tuesday April 20, 2021). Patient refused intravenous gammaglobulin infusion which has been ordered last night. Patient has been receiving dexamethasone which was a bridge until intravenous gammaglobulin could be administered. Current guidance from the expert hematology panel (EHP) on Covid vaccine induced thrombosis dated April 7, 2021 from the public health would state that a patient who has a reduced platelet count without thrombosis with a D-dimer normal and normal fibrinogen or thrombosis with a normal platelet count and D-dimer normal and normal fibrinogen are "unlikely cases". They recommend for probable cases who have D-dimers that are elevated to send HIT assay and then give immediate intravenous gammaglobulin while awaiting results. They recommend fibrinogen supplementation, if needed. They recommend a direct acting antithrombin agents such as the Eliquis this patient is receiving. They recommend steroids particularly if there is a delay in getting intravenous gammaglobulin delivered. With the fact that we now have 24 hours in the hospital with no evidence of thrombocytopenia, no evidence of increased fibrinolytic activity or active thrombosis, and no evidence of hypofibrinogenemia, I would argue that her presentation is subacute. In this setting, I do not feel intravenous gammaglobulin would be necessary and does involve a small risk as well as considerable cost. Dexamethasone also involves small risk and negligible cost. I have discontinued both of these medications. My overall impression would be that this was not related to her Johnson & Johnson vaccination which was recent, but rather her more distant Covid infection. It is impossible to definitively answer the question however. The next question is duration of anticoagulation. Risk of recurrent cerebral sinus venous thrombosis is relatively small but the morbidity can be high. Studies have been performed showing medications in the same class as Eliquis have been associated with a decrease in incidence of the recurrence. Most hematologist recommend 3 months of anticoagulation for provoked venous thrombosis including cerebral sinus venous thrombosis. I feel this patient''s thrombosis is "provoked", with her association at the same time of her Covid infection (and possibly vaccination). I would recommend Eliquis (apixaban) 5 mg twice daily or Xarelto (rivaroxaban) 20 mg daily with food. I would feel comfortable in discharging patient for outpatient follow up IF Dr and other speciality services agree. Plan 3 months of full dose anticoagulation with direct factor X inhibitor. Circulation 2010 Jun 29;121(25):2740-6 "Long-term evaluation of the risk of recurrence after cerebral sinus-venous thrombosis", Background: The clinical course of cerebral sinus-venous thrombosis (CSVT) is largely unknown because prospective studies with a long follow-up and with the goal to assess thrombosis recurrence rate and predisposing factors for recurrence are lacking. Methods and results: One hundred forty-five patients with a first CSVT were followed up for a median of 6 years after discontinuation of anticoagulant treatment. End points were recurrent CSVT or other clinical manifestations of venous thromboembolism. CSVT recurred in 5 patients (3%) and other manifestations of venous thromboembolism (deep vein thrombosis of the lower limbs or pulmonary embolism) were seen in 10 additional patients (7%), for a recurrence rate of 2.03 per 100 person-years (95% confidence interval, 1.16 to 3.14) for all manifestations of venous thromboembolism and 0.53 per 100 person-years (95% confidence interval, 0.16 to 1.10) for CSVT. Nearly half of the recurrences occurred within the first year after discontinuation of anticoagulant therapy. Risk factors for recurrent venous thrombosis were male sex (adjusted hazard ratio, 9.66; 95% confidence interval, 2.86 to 32.7) and, for thromboses other than CSVT, severe thrombophilia resulting from antithrombin, protein C, protein S deficiency, anti-phospholipid antibodies, or combined abnormalities (adjusted hazard ratio, 4.71; 95% confidence interval, 1.34 to 16.5). Conclusions: The risk of recurrent CSVT is low and is higher in the first year after discontinuation of anticoagulant treatment and among men. Mild thrombophilia abnormalities are not associated with recurrent CSVT, but severe thrombophilia entails an increased risk of deep vein thrombosis of the lower limbs or pulmonary embolism. April 19, 2021 Follow up, no change in condition. Discussed case with Dr, will order Factor V Leiden, prothrombin gene mutation, anti phospholipid and anti cardiolipin antibodies, if she will allow draw. Expect Heparin Induced Thrombosis testing result tomorrow, but with no thrombocytopenia after given heparin, expect will be normal. Will await result. If discharged, would recommend 3 months direct thrombin inhibitor (Eliquis/Xarelto/Pradaxa) at full anticoagulation dose. Then stop, no taper. Overall still feel "provoked" thrombosis due to December Covid, unrelated to J&J Covid vaccine, but can not definitively prove that..
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