Adjunct Immune Globulin for Vaccine-Induced Thrombotic Thrombocytopenia

Tom Smith

Platelet Changes after IVIG Figure 1. Figure 1. Clinical and Laboratory Data for the Three Study Patients with VITT. Serial platelet counts and coagulation tests for d-dimer and fibrinogen levels are shown in relation to clinical events in the three patients. The timing of blood samples obtained before and after […]

Platelet Changes after IVIG

Clinical and Laboratory Data for the Three Study Patients with VITT.

Serial platelet counts and coagulation tests for d-dimer and fibrinogen levels are shown in relation to clinical events in the three patients. The timing of blood samples obtained before and after the administration of intravenous immune globulin (IVIG) correspond to the performance of enzyme-linked immunosorbent assays and platelet-activation assays.

Panel A shows the findings in Patient 1, a 72-year-old woman in whom vaccine-induced thrombotic thrombocytopenia (VITT) was complicated by limb-artery thrombosis and partial celiac-artery thrombosis. The calculation of the IVIG dose was based on both weight and height, according to the “dosing weight” designation (1 g per kilogram of body weight) of the Ontario dose calculator.14 Thus, for a female patient weighing 59 kg with a height of 162 cm, the dose would be 55 g per kilogram, which the patient received. However, the first dose was divided into portions of 15 g and 40 g per kilogram, since the patient had an adverse reaction (severe chills) after the initial 15-g infusion of IVIG; the remaining 40 g per kilogram was given the next day without incident.

Panel B shows the findings in Patient 2, a 63-year-old man with VITT that was complicated by limb-artery thrombosis, pulmonary embolism, and deep-vein thrombosis. According to the “dosing weight” on the Ontario dose calculator, for a male patient weighing 158 kg with a height of 198 cm, the dose of IVIG would be 120 g per kilogram; the patient’s actual dose was 165 g per kilogram because the ordering physician opted to use a dose closer to the patient’s actual body weight.

Panel C shows the findings in Patient 3, a 69-year-old man with VITT that was complicated by stroke involving the right middle cerebral artery, cerebral venous sinus thrombosis (right cerebral transverse and sigmoid sinuses), and thromboses in the right internal carotid artery, right internal jugular vein, hepatic vein (main and left branch), and distal lower-limb vein (one branch of the left trifurcation), along with a diagnosis of pulmonary embolism. According to the “dosing weight” on the Ontario dose calculator, for a male patient weighing 140 kg with a height 185 cm, the IVIG dose would be 105 g per kilogram; the actual dose the patient received was 100 g per kilogram. A third dose of IVIG was given on day 24 because of concern regarding a partial loss of the IVIG effect, with possible exacerbation of VITT, since the patient’s platelet count fell from 125,000 to 106,000 per cubic millimeter and the d-dimer level increased from 14.8 to more than 20 mg per liter. After the third dose of IVIG, the platelet count rose to 165,000 per cubic millimeter, and the d-dimer level fell to 13.1 mg per liter. SC denotes subcutaneous, and UFH unfractionated heparin (which is shown in units per kilogram per hour in Patient 2; details regarding heparin dosing were not available for Patient 1).

Figure 1 shows serial platelet counts for the three patients in relation to treatment with anticoagulant and IVIG. Data regarding the patients’ height, weight, and dosing considerations for IVIG administration (according to the Ontario dose calculator14) are provided in the Figure 1 legend.

In Patient 1, the platelet count rose from 39,000 to 77,000 per cubic millimeter during treatment with intravenous heparin, which was stopped before surgery. The platelet count did not change postoperatively during the 5-day administration of argatroban. However, after the administration of IVIG, the platelet count rose from 74,000 to 114,000 per cubic millimeter during a 2-day period, at which time the patient was discharged while receiving oral apixaban. At a follow-up visit 9 days later, the platelet count had normalized at 166,000 per cubic millimeter. Although mild thrombocytopenia recurred during the next 3 weeks, the d-dimer levels normalized.

In Patient 2, the platelet count initially rose from 36,000 to 77,000 per cubic millimeter after the administration of intravenous heparin. Subsequently, the platelet count fell, and heparin was switched to fondaparinux. After treatment with IVIG, the platelet count rose from 27,000 to 124,000 per cubic millimeter during a 3-day period; 7 days after the initiation of IVIG, the platelet count was 640,000 per cubic millimeter.

In Patient 3, no initial heparin was given. After VITT was diagnosed, IVIG and fondaparinux were administered, which resulted in an increase in the platelet count from 35,000 to 125,000 per cubic millimeter during a 3-day period, followed by a decrease to 106,000 per cubic millimeter and an increase in the d-dimer level; after a third dose of IVIG (as shown in the fourth blood sample), the platelet count rose to 165,000 per cubic millimeter, and the d-dimer level fell once again.

None of the three patients had clinical evidence of new or progressive thrombosis after IVIG treatment.

Laboratory Testing

Two of the three patients (Patients 2 and 3) had evidence of disseminated intravascular coagulation, including elevated d-dimer levels (>10 and >20 mg per liter, respectively [reference range, <0.50]), low-normal fibrinogen levels (140 and 200 mg per deciliter, respectively [reference range, 160 to 420]), and a mildly increased international normalized ratio (peak, 1.3 and 1.4, respectively [reference range, <1.2]). These results met the criteria for overt disseminated intravascular coagulation.15 After treatment with IVIG, the two patients had a reduction in serial d-dimer levels and an increase in serial fibrinogen levels, findings that were consistent with decreased hypercoagulability.

Platelet Immunologic Analyses

ELISA Reactivity before and after Treatment with IVIG.

All three patients tested strongly positive for antibodies against PF4–polyanion complexes on ELISA (Table 1). No consistent reduction in ELISA reactivity was seen after treatment with IVIG, which indicated that IVIG did not inhibit VITT antibody binding to PF4. Patient 2 tested negative on a latex-based immunoturbidimetric assay (HemosIL HIT-Ab(PF4-H), Instrumentation Laboratory), a local rapid-screening test for HIT antibodies. According to a recent report,4 this screening test has shown negative results for VITT antibodies.

Results of Platelet-Activation Assays.

Panel A shows the results of a conventional platelet-activation assay for heparin-induced thrombocytopenia (a serotonin-release assay) in the three study patients. Platelet activation was inhibited in serum obtained from the three patients after treatment with IVIG. Panel B shows the results of a modified platelet-activation assay to detect VITT antibodies reactive against platelet factor 4 (PF4) in the three patients. Variable levels of inhibition of PF4-enhanced serotonin release were seen in patients’ serum obtained after treatment with IVIG. Complete inhibition was seen with the addition of FcγIIa receptor–blocking monoclonal antibody (IV.3) or the addition of IVIG at a concentration of 10 mg per milliliter.

Serum obtained before IVIG administration (baseline) in the three patients showed three different reaction patterns on the serotonin-release assay, the standard platelet-activation assay for HIT. Patient 1 tested weakly positive for HIT, with serum producing 19% serotonin release with heparin at a concentration of 0 U per milliliter, 41% at 0.1 U per milliliter, 23% at 0.3 U per milliliter, and 0% at 100 U per milliliter (Figure 2A). (On this assay, a positive result is a release of >20% with heparin at a concentration of 0.1 U per milliliter or at a concentration of 0.3 U per milliliter that is inhibited at 100 U per milliliter.) Testing of serum from Patient 2 showed an atypical result, with 35% serotonin release observed in the absence of heparin that was inhibited to less than 5% with the addition of heparin at a concentration of 0.1 U per milliliter and 0.3 U per milliliter. Testing of serum from Patient 3 also showed an atypical result, with serotonin release of 78% with heparin at a concentration of 0 U per milliliter and 72% at 0.1 U per milliliter. For all three patients, serum-induced serotonin release was not observed after one or two doses of IVIG.

In Patients 1 and 2, the addition of PF4 (10 μg per milliliter) to serum obtained at baseline showed strong (>80%) serotonin release (Figure 2B). No effect of PF4 was seen in the baseline serum from Patient 3, which showed a 78% serotonin release in the absence of PF4. In all three patients, serum that was obtained after IVIG treatment showed a reduction in reactivity in the presence of PF4; these reductions ranged from marked (in Patient 3) to minor (in Patient 2). Patient 2, whose serum showed the least reduction in serotonin release in the presence of PF4 after IVIG administration, had the greatest increase in the platelet count (from 27,000 to 640,000 per cubic millimeter during a 7-day period).

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