Severe thrombocytopenia in two children following split liver transplantation from the same donor with idiopathic thrombocytopenia

INTRODUCTION

Immune-mediated disorders can be transferred to recipients during solid organ transplantation by residual leukocytes from the donor organ. The most common form is passenger lymphocyte syndrome which provokes hemolytic anemia due to anti-A or anti-B produced by the lymphocytes present in the transplanted organ, in the case of ABO incompatibility between the recipient and donor. Transplantation-mediated alloimmune thrombocytopenia (TMAT) is an uncommon form of donor-derived thrombocytopenia following solid organ transplantation. Rarely described, this condition occurs following transplantation from a donor with immune thrombocytopenia (ITP) and may lead to hemorrhagic complications, graft failure, and even death^1–3. In this case report, we describe two children who developed severe, life-threatening thrombocytopenia after in situ split liver transplantation from the same donor.

CASE REPORT

Donor

The donor was a 13-year-old boy with ITP who sustained an intracranial hemorrhage and progressed to brain death. His blood group was A-positive, Rh (D) positive. His platelet count just before death was 2×10⁹/L. The donor received steroids, intravenous immunoglobulins, and rituximab and underwent splenectomy. The liver was split and the right triple-lobe (1,100 g) was donated to recipient 1 and the left lateral lobe (395 g) implanted into recipient 2 using the standard technique.

Recipient 1

Liver recipient 1 was a 12-year-old boy weighing 31 kg with decompensated cirrhosis and gastrointestinal bleeding. His blood type was group A, Rh (D) positive, with a negative red blood cell antibody screen. His preoperative platelet count was 47×10⁹/L, and platelet antibody screening was negative. The patient had no history of ITP.

There were no surgical complications, and the patient’s condition remained stable throughout the in situ split transplantation procedure. The cold ischemia time was 495 min and the anhepatic phase time was 65 min. All anastomoses were performed after modified piggyback liver transplantation. The estimated total blood loss during the procedure was 600 mL. The intraoperative blood component use included 8.5 units of packed red blood cells, 10 units of platelets, 1,000 mL of fresh-frozen plasma, and 10.5 units of cryoprecipitate.

The boy’s postoperative graft function was good, and he received piperacillin-tazobactam (2.25 g q12h) and vancomycin (0.5 g q12h). On postoperative day (POD) 1, his platelet count decreased from 47×10⁹/L to 6×10⁹/L. The prothrombin time was 12.6 s (normal range, 9.2 to 13.0 s); International Normalized Ratio, 1.2 (normal range, 0.8 to 1.5); and activated partial thromboplastin time, 24.3 s (normal range, 24.6 to 37.4 s). At that point, thrombocytopenia was thought to be a complication of the surgery, and the patient was transfused with one unit of platelets. However, on POD 2, the platelet count continued to fall to 2×10⁹/L, and antiplatelet antibodies were observed in the patient’s serum. Plasma exchange (1,300 mL) was initiated on POD 3 to eliminate the antibodies. Caspofungin (70 mg) was administered as an anti-infective agent. Treatment with intravenous immunoglobulins and pulse methylprednisolone was then started but did not trigger a sustained increase in the platelet count (Figure 1A). The patient suffered severe hemorrhagic complications, with scattered purpura on the skin throughout the body. Three days after the unsuccessful intensive medical therapy, the patient was listed for urgent re-transplantation. Fortunately, suitable liver tissue was available. Emergency re-transplantation was undertaken on POD 3. The surgery was performed without complications. The liver graft was a split right triple-lobe (800 g). The cold ischemia time was 615 min and the anhepatic phase time was 75 min. Surgical medications included basiliximab (20 mg) and methylprednisolone (300 mg). The estimated total blood loss during the procedure was 800 mL. The intraoperative blood components included 4 units of packed red blood cells, 10 units of platelets, 1,150 mL of fresh-frozen plasma, and 10 units of cryoprecipitate. After the second transplantation, the patient received anti-infection therapy comprising meropenem (0.5 g q8h), vancomycin (0.5 g q12h), caspofungin (70 mg qd) and immunosuppressive therapy with tacrolimus, mycophenolate mofetil and glucocorticoids. Other treatments included high-dose steroids, gamma-globulin, plasma exchange and platelet transfusion. Antiplatelet antibodies were negative on POD 5. Graft function was good, and his platelet count increased steadily (Figure 1A). The patient was discharged on day 25 after re-transplantation, with a platelet count of 190×10⁹/L. After 6 months of follow-up with standard immunosuppressive therapy, TMAT did not relapse.

Figure 1.

Platelet count and timing of treatment and platelet antibody studies during hospitalization

(A) Recipient 1; (B) Recipient 2. Black arrows: plasma exchange; green arrows: negative platelet antibodies; red arrow: positive platelet antibodies; blue arrows: platelet transfusion.

Recipient 2

Liver recipient 2 was a 3-year-old boy with an A-positive blood group, weighing 16 kg, with biliary atresia and cholestatic cirrhosis, splenomegaly, and favism. His preoperative platelet count was 79×10⁹/L, with normal coagulation function.

The patient’s surgical procedure was uneventful. The cold ischemia time was 310 min and the anhepatic phase time was 43 min. Medications administered in the anhepatic phase were basiliximab (10 mg) and methylprednisolone (160 mg). All anastomoses were performed after piggyback liver transplantation. The estimated total blood loss during the procedure was 200 mL. Intraoperative blood components administered included 2 units of packed red blood cells, 5 units of platelets, 400 mL of fresh-frozen plasma and 3 units of cryoprecipitate. The patient was transported to the intensive care unit. The medications administered postoperatively included imipenem (240 mg, q6h), vancomycin (160 mg, q6h), and ganciclovir (80 mg, q12h). The platelet count decreased from 79×10⁹/L to 25×10⁹/L on POD 1 and continued to decrease to 2×10⁹/L on POD 2. Anti-platelet antibodies were detected in the patient serum. The patient then received 0.5 units of platelets twice, which produced a transient increase in the platelet count to 19×10⁹/L. At that point, ITP was thought to be a complication of surgery, and intravenous immunoglobulins (5 g) and pulse methylprednisolone (20 mg/kg once) were initiated. After 2 days of intensive medical therapy, the boy’s platelet count did not increase significantly (Figure 1B). Plasma exchange was performed to eliminate antiplatelet antibodies on POD 2, 4 and 6. Basiliximab was administered on POD 4. Antiplatelet antibodies were negative on POD 8. The platelet count gradually improved and returned to the normal range on POD 11, as shown (Figure 1B). The patient was discharged on POD 51 with a platelet count of 143×10⁹/L. The platelet count remained between 110 and 150×10⁹/L until 6 months of follow-up with standard immunosuppressive therapy.

DISCUSSION

Thrombocytopenia following liver transplantation is a common condition that may be related to allograft sequestration, disseminated intravascular coagulation, sepsis, drugs, infections, and hypersplenism⁴. However, the development of severe, isolated thrombocytopenia after liver transplantation is unusual⁵. In our case, two pediatric recipients received liver transplants from the same donor in different hospitals, and both had a rapid decline in the platelet count after transplantation. Moreover, neither child exhibited any clinical or microbiological evidence of sepsis, and coagulopathy was ruled out. No evidence of thrombotic microangiopathy or drug-induced thrombocytopenia was found. Several cases of thrombocytopenia have been reported after solid organ transplantation, especially of the liver, from donors with autoimmune thrombocytopenia (Table I)^1–3,6–9. Donor-derived thrombocytopenia resulting from solid organ transplantation is termed TMAT and is a form of passenger lymphocyte syndrome that, instead of affecting red blood cells, due to the characteristics of the antibody, impacts the platelets. In the reported cases of this type of TMAT, severe thrombocytopenia (<10×10⁹/L) always started within 3 days of transplantation and platelet antibodies were always detected in the serum of both the donor and recipient. In our case, identification of the antiplatelet antibody in the donor and recipients supported the diagnosis. After re-transplantation of recipient 1 and plasma exchange treatment of recipient 2, the antiplatelet antibodies disappeared. Subsequently, the platelet counts of the two recipients increased steadily. The clinical pictures and laboratory findings led us to conclude that our patients developed thrombocytopenia likely caused by donor lymphocytes from the liver allograft, leading to alloimmune platelet destruction and thrombocytopenia.

Table I.

Clinical characteristics of patients with transplantation-mediated alloimmune thrombocytopenia after liver transplantation

Authorref, year	Donor	Recipient	Pre-Tx PLT count (×109/L)	Nadir post-Tx PLT count (×109/L), time	Anti-platelet antibodies detected	Treatment	Outcome
	Diagnosis, age, gender, cause of death	Diagnosis, age, gender
Friendet al.8, 1999	ITP, 44 y, male, ICH	Primary biliary cirrhosis, 47 y, female	461	2, POD 3	GPIIb/IIIa in donor and recipient	High-dose steroids, IVIg, plasma exchange, liver re-Tx	PLT count normal after re-Tx
Torreet al.2, 2004	ITP, 37 y, male ICH	Decompensated HCV cirrhosis, 52 y, male	149	2, POD 0	PAIgG in recipient	IVIg	PLT increased to 46 on POD 5 and normal at 24 month
Diazet al.6, 2008	ITP, 52 y, male, ICH	Cirrhosis secondary to HCV, 67 y, male	22	6, POD 1	PAIgG in recipient	IVIg, rituximab, vincristine splenectomy, liver re-Tx	PLT recovered after re-Tx. Died within 2 months of discharge from septic complications
Pereboomet al.1, 2009	ITP, 53 y, male, ICH	Ischemic-type biliary lesions and recurrent cholangitis, 44 y, male	424	6, POD 3	Donor and recipient (specificity not stated)	Prednisone, IVIg	Acute portal vein thrombosis. Died
Kaestner and Kutsogiannis7, 2013	ITP, 71 y, male, ICH	Hepatocellular carcinoma and alcoholinduced cirrhosis, 58 y, male	90	5, POD 3	GPIIb/IIIa in donor and recipient	Methylprednisolone, IVIg, prednisone	PLT count increased slowly, discharged from hospital on post-Tx day 17
Hillet al.3, 2016	ITP, 73 y, male, ICH	Decompensated alcohol related liver disease, 61 y, male	72	2, POD 2	GPIb/IX in donor and recipient	IVIg, steroids, rituximab, romiplostin, plasmapheresis, vincristine, SAE, rFVII	Died on POD 18 with multiorgan failure
Elenaet al.9, 2021	ITP, 49 y, female, ICH	Alcoholic cirrhosis and portal hypertension, 50 y, male	116	2, POD 2	GPIIb/IIIa in recipient	Steroids, IVIg, re-Tx	PLT recovered after re-Tx. Alive at 1 year

ITP: immune thrombocytopenia; ICH: intracranial hemorrhage; HCV: hepatitis C virus; IVIg: intravenous immune globulin; PLT: platelet; POD: postoperative day; rFVII: recombinant factor VII; SAE: splenic artery embolization; Tx: transplant; y: years

The optimal treatment for TMAT is unclear because few cases have been described. Transplantation of the liver from a donor with ITP should be considered with great caution¹⁰. The recipients must be followed carefully for evidence of immune thrombocytopenia, and treatment must be offered accordingly. The clinical management of TMAT typically involves laboratory investigation of the organ donor, and follow-up of the recipient is critical for diagnosing the etiology of the thrombocytopenia. Medical therapy must be initiated rapidly and includes intravenous immunoglobulins, rituximab, plasma exchange, and random platelet transfusion. The use of rituximab to prevent rejection after liver transplantation may reduce complications and improve prognosis. Early re-transplantation should be considered to prevent severe hemorrhagic complications if the condition does not respond to treatment within 2–3 days⁹. In our case, recipient 1 and recipient 2 underwent transplantation in different hospitals. Although recipient 1 was older than recipient 2, he experienced severe hemorrhagic complications after 3 days of unsuccessful intensive medical therapy. Re-transplantation was the optimal choice under these conditions. Recipient 2 had a good reaction to plasma exchange, so re-transplantation was not considered.

In conclusion, we describe a rare case of severe thrombocytopenia in two children after liver transplantation from an ITP donor. We emphasize the importance of considering TMAT in the differential diagnosis of thrombocytopenia occurring after liver transplantation, especially when the donor is diagnosed with ITP. Early plasma exchange and re-transplantation should also be considered. Laboratory investigations of the organ donors and recipients are critical for diagnosing the etiology of the thrombocytopenia.