Clinical Profile, Treatment and Outcome of Thrombotic Thrombocytopenia Purpura (TTP) in Rituximab Era- an Experience from Tertiary Care Centre from North India

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia (MAHA) resulting from severe deficiency of ADAMTS13. TTP is an acute medical emergency which requires early treatment with therapeutic plasma exchange. With the early use of Rituximab along with PLEX, early response is achieved and relapse rate has gone down. There is lack of published data from India regarding treatment and outcome of TTP. We retrospectively analyzed our data of 21 patients of TTP including 4 patients who had TA-TMA. TTP patients were treated with TPE, pulse methylprednisolone and rituximab. After a median follow up of 57.5 months overall survival in TTP patients was 82.3% in our study and one patient relapsed twice but again responded to same treatment. Relapse free survival was 92.8%. The mortality rate in our study in TTP patients was (3/17) 17.6%. The total response rate was 82.3% (14/17). Out of 4 patients of TA-TMA, Only 33.3% patients responded to plasma exchange in TA-TMA while two patients died (2/4) 50%. Immediate TPE and early rituximab are associated with improved survival in TTP patients, however TA-TMA still remains a significant challenge for transplant physicians and more research is needed in guiding the therapy.

Introduction

Thrombotic thrombocytopenic purpura (TTP), results from severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13). ADAMTS13 is a von willebrand factor cleaving protease and low levels of ADAMTS13 results in micro thrombi formation resulting in end organ ischemia and damage [1, 2]. Although a classical pentad of fever, thrombocytopenia, MAHA, neurological symptoms, and renal insufficiency is described for identifying TTP, it is seen in < 10% patients [2]. It is suspected in the presence of MAHA as evidenced by presence of schistocytes in the blood along with thrombocytopenia. ADAMTS13 activity of < 10% confirms the diagnosis of TTP [1]. Primary TTP occurs in isolation and secondary TTP is associated with a predisposing condition like autoimmune diseases (Systemic lupus erythematosus), malignancy, infection (HIV), pregnancy and certain drugs (Gemcitabine) [3].

Therapeutic plasma exchange (TPE) is the main stay of treatment and should be started at the earliest to prevent mortality [4]. TPE is continued until resolution of symptoms and recovery of platelet counts [5]. ADAMTS13 assay is not available in most centers and is outsourced resulting in long turnaround time. Thus, in most centers in India, the decision to start therapeutic plasma exchange (TPE) is usually dependent on clinical judgment. However there are few scores like ‘Plasmic score’ which help to predict TTP at admission and stratify the patients according to risk of having severe ADAMTS13 deficiency and requiring TPE [2]. TTP is also a well known entity after allogenic bone marrow transplant. However ADAMTS13 activity never reaches below 10%. Risk factors associated with transplant associated -thrombotic microangiopathy (TA-TMA) includes the use of Calcineurin inhibitors, viral infections, active graft versus host disease, and fungal infections [6]. Here we report our data of 21 patients of TTP including 4 cases of post transplant TMA.

Methods

A retrospective review of patients diagnosed as TTP was done from January 2018 to October 2023. Clinical, laboratory and treatment outcome data was collected from hospital information system. Schistocyte quantification was done using the International Society of Laboratory Hematology (ISLH) guidelines [7]. For the diagnosis of TTP, schistocyte index of more than 1% was taken as cutoff [7] whereas for TA-TMA, CIBMTR criteria was used for the diagnosis [8]. The ADAMTS13 level and inhibitor assay was outsourced to an accredited laboratory. Clinical features, treatment and outcome of these patients including number of TPE procedures were noted. Primary endpoint was complete response rates and secondary end points were number of PLEX cycles, relapse rate and overall survival. Continuous data were presented as medians (ranges) and categorical data were presented as numbers and percentages.

Results

Twenty one patients were diagnosed with thrombotic Thrombocytopenic Purpura during the study period. In all the patients, diagnosis was made by clinical criteria. Demographic, clinical and treatment outcome data is shown in Table 1. Out of 21 patients, ADAMTS13 levels were done in 17 patients solely on the basis of clinical suspicion. All had ADAMTS13 levels below 10% consistent with the diagnosis of TTP. Rest of the four patients had TA-TMA and ADAMTS13 levels were not available for these patients. Of these 17 patients of TTP, 13 were females and 4 were males. Among the TTP group, median age at presentation was 44 years (25–64). Median hemoglobin was 8.3 g/dl; range (6.5–10.6) total leukocyte count 10.36 × 10⁶ /l range (5.96–22.65) platelet count was 12 × 10 ⁹ /l; range (0.04–0.35) at the time of presentation. Median schistocyte index was 5.6% (2.5–22). Eight (47%) patients had secondary TTP (7 had SLE and one had HIV) and 9 (52.9%) had primary TTP. The triad of thrombocytopenia, microangiopathic haemolytic anemia and neurological features at presentation was present in 76% of the patients. The classical pentad was not present in any one the patient. Abnormal bleeding including petechiae, ecchymoses and mennorhagia was present in six patients (35.2%) of the patients. Three patients had abnormal findings on neuroimaging. Acute renal failure was not present in any of the patients which help them to differentiate from HUS. Median numbers of plasma exchange cycles were 9. All of these patients received TPE and pulse methylprednisolone 1 g/kg for 3 days followed by tapering doses of oral prednisolone as the first line of treatment. Sixteen patients received Rituximab and one did not receive due to active HIV infection. Ten patients received four weekly doses of Rituximab while three patients received only one dose of Rituximab and one patient received only two doses. Among the 17 patients with TTP, 1 patients did not respond to PLEX and three (17.6%) among these died within first week of treatment due to non responsive disease. After a median follow up of 57.5 months (12–96) overall survival in TTP patients was 82.3% in our study. One patient relapsed twice; first relapse was after 18 months but again responded to PLEX, steroids and four doses of Rituximab and second relapse after 36 months and again responded completely to the same treatment. Amongst the four patients who had TA-TMA, 3 were males and one was female. Median age at presentation was 39.5 years. Median Hemoglobin, TLC and platelet count were 9 g/dl, 7.6 and 0.095respectively at the time of episode of TMA. All the four patients had active CMV disease, 2 had active GVHD at the time of presentation. Three patients received plasma exchange along with treatment of active GVHD and CMV disease. Two patients amongst these died and one recovered with PLEX. Another one patient recovered with withdrawal of CNI. The clinical and treatment outcome is shown in Table 1.

Table 1.

Clinical profile and treatment outcome in TTP patients

Case	Age	Gender	Clinical presentation	HB g/dl	TLC X 10 6	PLTx 10 9	SI (%)	LDH (≤ 220IU)	Cr mg/dl	PLEX No.of cycles	RTX No of doses	Response	outcome	Fu (mon
1	51	M	Fever, seizures	8.2	6.14	14.0	13	996	1.97	3	No	RR	Expired	-
2	56	F	Headache/ petechia	6.5	5.96	30.0	5.2	580	0.2	3	4	CR	Alive	25
3	50	M	Fever, slurring speech	8.7	13	13.0	7.2	763	0.9	4	4	CR	Alive	70
4	64	F	altered sensorium	8.1	8.4	5.0	2.6	896	0.99	5	1	RR	Expired	-
5	57	F	Altered sensorium	7.7	9.5	26.0	4.3	753	0.74	5	1	RR	Expired	-
6	51	F	Fever, headache, bleeding gums	8.3	9.83	18.0	5.6	1080	0.8	7	4	CR	alive	62
7	29	F	Mennorhagia,	10.1	10.88	9.0	4.6	2661	1.28	8	4	CR	Alive	38
8	26	F	Altered sensorium	7.0	9.0	10.0	6.8	656	1.2	8	4	CR	Alive	12
9	30	F	Mennorhagia	8.6	11.34	6.0	15	1274	0.8	8	4	CR	Alive	53
10	44	F	Seizures,	10.6	1.036	14.0	22	1501	0.75	8	12/relapsed twice	CR3	Alive	63 Relapsed twice
11	41	F	Headache, facial deviation	10	22.65	7.0	6.8	943	1.21	8	1	CR	Alive	62
12	25	F	Seizures/ bleeding pupura	6.6	14.79	10.0	9.6	2957	0.5	10	4	CR	Alive	24
13	35	F	Fever	8.3	8.1	12.0	2.5	1346	0.68	12	4	CR	Alive	96
14	43	F	Fever, vomittng, seizure	9.1	13.39	9.0	5.3	685	1.29	12	2	CR	Alive	86
15	38	M	Slurring of speech	7.5	12.10	22.0	6.2	1206	1.37	12	4	CR	Alive	88
16	57	M	Seizure,	8.3	7.26	35.0	9.7	1836	1.5	16	4	CR	Alive	20
17	44	F	Mennorhagia,	7.2	15.72	4.0	6	312	0.5	16	4	RR	Alive	29
18	33	M	Day 96 BMT Fever, hypotension, seizure, active CMV	7	7.2	3.0	5	501	0.91	4	0	CR	Alive	79
19	45	F	Day 32 BMT, PneumocystitisPneumonia, active CMV	9.6	8.0	8.0	3.2	1117	1.79	3	0	RR	expired	-
20	34	M	Day 180 BMT, gut GVHD, active CMV	8.8	4.55	11.0	3.94	795	3.94	1	0	RR	expired	-
21	45	M	Day 195 BMT, thrombocytopenia, active CMV	9.2	16.5	52.0	2.5	1391	0.98	0	0, Withdrawal of CNI	CR	Alive	5

Hb hemoglobin, TLC total leukocyte count, PLT platelet count, SI schistocyte index, LDH lactate dehydrogenase, Creat Creatinine, PLEX plasma exchange, RTX Rituximab, Fu Follow up

Discussion

Since TTP is a medical emergency, timely identification is an utmost clinical need [2]. It requires prompt treatment with plasma exchange at the earliest clinical suspicion as turn out around time for ADAMTS13 levels is long as test is not available in-house in most of the centers and is outsourced. In our study, out of total 21 patients, there were 14 females and males were 7. Female preponderance is explained owing to autoimmune etiology of acquired TTP. Also secondary TTP was present in 47% of the TTP patients. This data is in concordant with the literature published by various registries [9]. In one of studies from Jordan, 21 patients of TTP were studied and they found median schistocyte index of 6% which was comparable to our data of 6% [10]. The incidence of neurological signs, renal failure and bleeding in our study is comparable to that published in the literature [11].

TPE has been the only life saving treatment for TTP. All of our patients received TPE. 80% of the patients received TPE within 24 h of their presentation to hospital based only on high clinical suscipion. Various scores are reported in literature to supplement the clinical suspicion of TTP and to start TPE at the earliest. We used Plasmic score which was found to be high in all of our proven TTP patients. In a retrospective 10 year cohort study, median time from suspected diagnosis to first plasma exchange was 10.7 h. Delayed plasma exchange between 8 and 24 h was not associated with higher risk of death in their analysis [12]. 82.3% of the patients responded completely to TPE. Median number of TPE sessions varies widely ranging from 4- 10 sessions [12, 13]. In our study, median 9 sessions of PLEX were done. Sixteen patients received Rituximab and 80% of the patients received rituximab within first week of plasma exchange initiation. Also it has been reported that early Rituximab significantly reduces the relapse rates and significantly decreases the mortality rate which is corroborative of our data in which only one patient relapsed out of 14 patients who are alive [14]. All of our patients received standard dose pulse methylprednisolone followed by tapering doses of oral steroids. Although the level of evidence for the use of steroids in TTP is less as compared to that of Rituximab. However there are no comparable studies of TTP treatment with or without steroids [15]. In our study 3 patients died and 1 did not respond to TPE. One patient amongst these had active HIV disease with high viral load and all of these patients died within one week of hospitalization. One patient had refractory TTP post PLEX, steroids and 4 doses of Rituximab, schistocytes disappeared and LDH normalized but severe thrombocytopenia persisted likely converted to refractory ITP. After a median follow up of 57.5 months overall survival in TTP patients was 82.3% in our study and relapse free survival was 92.8%. The mortality rate in our study in TTP patients was 17.6%. In a retrospective study from USA, 30-day mortality was 16% which was comparable to our data. The rate of complete response was 65% which was slightly lower than our data. The rate of relapse was 18% which was higher than our relapse rate [16].

TA-TMA is a complication of HSCT which is more common after allogenic BMT [6]. The exact incidence of TA-TMA remains unknown, varying between 0.5% and 76% in allogenic BMT [17]. As per published literature, median time of onset varies between day 32 and 86 days [18]. Our patients had median time of onset was at day 86. Post transplant risk factors included acute GVHD, CMV disease and other infections, use of calcineurin inhibitor as gvhd prophylaxis [19]. All the four patients had active CMV disease and one amongst these had Pneumocystis jiroveci pneumonia, 2 had active GVHD at the time of presentation. One patient responded to withdrawal of CNI and rest of the three patients received plasma exchange. Two among these succumbed to infections and one responded to treatment and is healthy and in follow up. One of the studies of TA-TMA in allogenic BMT reported low response rate of 37% and high mortality rate of 79% [20]. Our response rate is also similar to previous study. In a retrospective study by Young et al., 66 patients of TA-TMA, 60% experienced response to PLEX and six month survival was 0% who were non responders [21]. Multicentre clinical trials are needed for treatment optimization in patients with TA-TMA.

Conclusion

TTP is a medical emergency with high mortality. Urgent treatment with plasma exchange is the standard of care and early use of Rituximab appears to be well tolerated. For the treatment of TA-TMA, larger multi centre studies are needed in view of varied pathogenesis and etiology of TA-TMA.

Author Contribution

Serial No		Name of author	Department	Contribution
1	Deepika Gupta		Clinical Haematology and BMT	Work up of cases, Drafting manuscript and management
2		Priyanka Moule	Clinical Haematology and BMT	Work up of cases
3		Vivek Ranjan	Blood transfusion Medicine	Support for Plasma exchange
4		Jyoti Kotwal	Laboratory hematology	Reporting of peripheral smears
5		Kamini Khillan	Blood transfusion Medicine	Support for Plasma exchange
6		Amrita saraf	Laboratory Haematology	Reporting of peripheral smears for schistocyte index
7		Sabina Langer	Laboratory Haematology	Reporting of peripheral smears for schistocyte index
8		Pallavi prakhar	Laboratory Haematology	Reporting of peripheral smears for schistocyte index
9		Nitin Gupta	Clinical Haematology and BMT	Work up and management of cases and drafting of manuscript