Panacea Journal of Medical Sciences

Introduction   

Phlebotomy, also known as bloodletting or venesection, is a major therapeutic procedure that has been performed by physicians since antiquity up to the present. ^[1], ^[2] Currently, there are three main indications for therapeutic phlebotomy i.e., haemochromatosis, polycythaemia vera (PV) and porphyria cutanea tarda (PCT)^[3] along with sickle cell disease, some cases of secondary polycythaemia like post renal transplant patient and cyanotic heart disease and hypoxic conditions like chronic lung disease.

As per 2016 WHO criteria, PV can be suspected in any person with an increase in haemoglobin level (more than 16.5 g/dL or 16 g/dL in men and women, respectively) and increase in haematocrit level (> 49% in men and >48% in women respectively) or an increase in red blood cell count and JAK2 mutation. ^[4]

Phlebotomy is now considered to be the main stay of treatment in PV. Some studies suggested that haematocrit level should be maintained below 45% to reduce the risk of vascular occlusive episode. ^[5] Phlebotomy has been used for the treatment of secondary polycythaemia in patients with chronic obstructive pulmonary disease. It results in an improvement of cerebral perfusion as well as sensory and mental function by lowering blood viscosity. ^[6] Treatment for post-transplant erythrocytosis includes angiotensin-converting enzyme inhibitor or an angiotensin II receptor antagonist, or venesection with a target haematocrit less than 45%. ^[7] Patients with a cyanotic congenital heart disease, such as Eisenmenger’s syndrome or Tetralogy of Fallot, develop erythrocytosis secondary to their cyanosis. In 2008, the American College of Cardiology/American Heart Association published guidelines and recommended performing therapeutic phlebotomy for symptomatic patients with haemoglobin and haematocrit values greater than 20 g/dL and 65%, respectively, while taking care to avoid iron depletion. ^[8]

One of the main indications for therapeutic phlebotomy is haemochromatosis. A large survey that included 2,851 patients with haemochromatosis to assess the symptoms and the response to therapeutic phlebotomy found that 86% of cases had some or all of their symptoms improved with phlebotomy with an average time for improvement of 39±67 weeks.^[9] Therapeutic phlebotomy has long been considered the treatment of choice in most patients with PCT. ^[10] Phlebotomy decreases the viscosity of blood by reducing the haemoglobin level and thus reduces HbS molecule polymerisation in sickle cell disease. ^[11] Patients with metabolic syndrome who underwent iron reduction by phlebotomy had statistically significant differences in systolic blood pressure, glucose, HbA1c, HDL cholesterol, iron and ferritin compared to controls (p<0.001). ^[12]

Aims and Objective

The aim of the study is to evaluate the effect of therapeutic phlebotomy on haematological parameters and also its role in clinical outcome. The objectives of our study are to

To formulate the treatment decisions and guidelines basing on patient condition.

Prevent the complication of patients and decrease the mortality rate among the patients.

Materials and Methods

The study was conducted in the Phlebotomy section of department of Transfusion Medicine, Sriram Chandra Bhanja (SCB) Medical College &Hospital, Cuttack, Odisha.

Result

In total, 393 procedures of phlebotomy were conducted over 55 cases. Out of these, 41 (74.5%) cases were of PV, 13(23.6%) cases of secondary polycythaemia and only one case of high serum ferritin secondary to bone marrow transplant. Again, out of these 41 cases of PV, two special conditions were associated with PV, one was pregnancy & other was HIV.

In this study, erythrocytosis was more commonly seen in male in comparison to female (47:7 that was (6.7:1). In PV male to female ratio was 5.9:1 whereas in secondary polycythaemia it was 12:1.As per WHO-2016 guideline of diagnosis of PV, JAK-2 mutation is a minor criterion. In this study there were 30(73%) cases with JAK-2 mutation and 11(27%) cases were without this gene mutation. In this study, serum erythropoietin level was measured in every PV cases. Out of total 41 cases, 44% patients had normal s.epo level,47% patients had low s.epo level and 9% patients had high s.epo level.

The most common cause of secondary erythrocytosis in this study was cyanotic heart disease 5 cases (38%) followed by pulmonary disease 3 cases (23%), post renal transplant 2 cases (15%), medical renal disease, metabolic syndrome and hypertension in young patient each constituting one case (7%).Most of the PV cases belonged to age group of 40- 59years ,18 cases (43%), followed by 20-39years 12 cases (29%), more than 60years 10 cases (24%) and only one case of age group less than 20years. In the secondary erythrocytosis cases group, there was no case above 60 years of age, only 9 cases of 20-39 years age, 3 cases of less than 20years and only one case of age group 40-59.

In the PV cases, 58% belonged to 40-60kg weight group followed by 34 % had more than 60kg and only 7% had less than 40 kg weight. All the 13 cases of the erythrocytosis were equally distributed in these mentioned weight group. In this study population, most of the cases (34.5%) belonged to O blood group, followed by B (32.7%), A (23.6%), AB (7.2%) blood groups.

The presenting laboratory findings of these study population were raised Hb (18.7±2.1), haematocrit (57±6.6), and/or subnormal level of erythropoietin (6.6±9.57) mU/ml. There were 30(73%) cases of PV having JAK-2 mutation and 31(77%) cases with Panmyelosis. [[Table 1]]

In this study, most common presenting symptom was weakness 51%, followed by headache (49%), pruritus (34%), dizziness (27%), weight loss (17%), breathlessness, joint pain & epigastric pain each 14%, numbness (12%) and myalgia (7%). In present study, about 34 % (17) of cases were found accidentally during a routine check-up. We detected skin plethora in 80% cases, splenomegaly in 73% cases, 70% cases with systolic BP >140mm Hg, 48% cases with high diastolic BP>90, 54% cases with conjunctival plethora and 36% cases of hepatomegaly.

Out of the 393 procedures, only 35 (9%) number of procedures had adverse reaction after phlebotomy. Vasovagal reaction (5.6%) was the most common adverse reaction after phlebotomy followed by hematoma (2.2%), bruise (1.7%) and thrombophlebitis (0.7%). Out of these adverse reactions, 3 patients showed same type of reaction repeatedly.

In this study, vitals of the patient and the presenting Hb & Hct were recorded. The presenting median Hb was 18.7gm/dl (IQR: 2.1), Hct was 57 % (IQR: 6.6), Systolic BP (130±18) mm of Hg, Diastolic BP (88±12) mm of Hg, PR (88±12) per minute. After a single procedure of phlebotomy, the Hb, Hct, Systolic & Diastolic BP, PR was reduced to (17.9±2) gm/dl, (54.2±6.7) %, (124±24) mm of Hg, (84±14) mm of Hg, (82±10) per minute respectively. [[Table 2]]

In this study we preferred IV fluids in cases of PV having low BP and other complications and in only cyanotic heart disease cases having secondary polycythaemia. Other cases were given oral fluid replacement. No significant changes seen (BP, PR) after removal of one unit of blood.

After 393 procedures, with a mean of 6 procedures for each patient, there was reduction in Hb, Hct, WBC, RBC, TPC ,Ferritin from (18.7± 2.1)gm/dl, (57±6.6 )%, (10.5±5.9)10³/µl, (6.9±1.8)10⁶/µl, (458.5±312)10³/µl, (246.05±84.4)ng/dl to (14.9±1.91)gm/dl, (46.1±4.1)%, (7.35±4.4)10³/µl,( 5.1±1)10⁶/µl, (304.5±243)10³/µl, (195±98.3)ng/dl respectively. [[Table 3]]

After an average 8 procedure of therapeutic phlebotomy in PV cases, the serum ferritin level decreases to lower normal limit, 7 cases developed iron deficiency, which was managed by giving regular folic acid. In this study 7 (17%) cases of PV were having hyper viscosity related complication like thrombosis (3=7.3%), stroke (3=7.3%) and portal hypertension (1=2.4%). All these cases presented with a Hct more than 50%.

With a median 6 number of therapeutic phlebotomies, aspirin & hydroxyurea in PV cases, 30 (73.1%) cases achieved the target Hct level. But there was again elevation in the Hct level in 9 (21.9%) cases of PV out of these 30 cases who had achieved the target. 11cases (26.8%) did not attain the target Hct level. In secondary erythrocytosis cases target Hct level was attained in 9 cases (69.2%) but again one case went out of the target Hct>45%. 4cases (30.7%) cases did not achieve the Hct <45%.

The progression of the PV to thrombosis was found in 17% cases, followed by MPN in 5% cases & Myelofibrosis in 5% cases. The symptoms were relieved in 7 cases with achieved target, and 2 cases without achieving target Hct <45. Out of the 4 cases who did not achieve the target Hct level, two cases of cyanotic heart disease patient developed iron deficiency after an average of 10 procedures and they were managed by iron & folic acid one case of TOF died because of congestive cardiac failure (CCF).

In this study, there was only one case of high serum ferritin level (>2840 ng/dl) due to post bone marrow transplantation. This was a 9 yr old female child weighing 35kg, having B Positive blood group, had beta thalassemia major. Only 2 therapeutic phlebotomy procedures (weekly once) could be done in this case, she could not be followed up for next procedure. After two procedures the serum ferritin level reduced to 2550ng/dl. [[Table 4]]

Discussion

The incidence of PV in the present study was 2.9 per 1 Lakh, which was similar to Verma S et al. ^[13] (4.7%) and Ania BJ et al. ^[14] (1.9 per 1Lakh). There were 13(23.6%) cases of secondary polycythaemia and only one case of high serum ferritin following bone marrow transplant.

In this study, erythrocytosis was more commonly seen in male in comparison to female (6.7:1). In our study, male to female ratio in PV cases was 5.9:1 which was little more (1.2 to 2.2) as compared to Ania BJ et al., ^[14] Berlin NI et al., ^[4] Modan B et al. ^[15] where as in secondary polycythaemia it was 12:1. In our study 30(73%) cases had JAK-2 mutation and 11(27%) cases were without this gene mutation, which is similar to the findings of Sazawal S et al. ^[16] (82%) and Varma S et al. ^[13] (81.8%). But Vainchenker W et al. ^[17] reported higher prevalence of JAK-2 mutation i.e., about 95% in PV cases.

The most common cause of secondary erythrocytosis was cyanotic heart disease 5 cases (38%) followed by pulmonary disease 3 cases (23%), post renal transplant 2 cases (15%), medical renal disease, metabolic syndrome and hypertension in young patient each constituting one case (7%). These conditions are similar as described by McMullin et al.^[8] Most of the polycythaemia vera cases were belonging to age group of 40-59years (43% cases) with a median age of 46 year (IQR 22.5) followed by 20-39years (29%), more than 60years (24%) and only one case of age group less than 20years. This finding of median age was less as reported by Berlin NI,^[4] Tefferi A (60Years). ^[18]

The presenting laboratory findings of these study population were raised Hb (18.7±2.1) gm/dl, Haematocrit (57±6.6) %, and/or subnormal level of erythropoietin (6.6±9.57) mU/ml. These findings were similar as reported by Perkins J et al., ^[19] London IM et al. ^[20] Birgegard G et al. ^[21] There were 30(73%) cases of polycythaemia vera having JAK-2 mutation and 31(77%) cases with Panmyelosis which was similar to Ellis JT et al. ^[22] There were 33% cases with normal cellularity which was slightly higher than Washerman LR et al. (13%). ^[23]

In this study, most common presenting symptom was weakness 51%, followed by headache (49%), pruritus (34%), dizziness (27%), weight loss (17%), breathlessness, joint pain & epigastric pain each 14%, numbness (12%) and myalgia (7%) which was similar to the findings by Berlin et al.^[4] Skin plethora was detected in 80% cases, splenomegaly in 73% cases, 70% cases with systolic BP >140, 48% cases with high diastolic BP>90, 54% cases with conjunctival plethora and 36% cases of hepatomegaly. All the detected signs were similar with the study of Berlin et al. ^[4] Vasovagal reaction (5.6%) was the most common adverse reaction after phlebotomy followed by hematoma (2.2%), bruise (1.7%) and thrombophlebitis (0.7%). But Cook LS et al. ^[3] and Roback J et al. ^[24] reported that hematoma was the most common adverse reaction after phlebotomy followed by syncope.

In this study 7 (17%) cases of polycythaemia vera were having hyper viscosity related complication like thrombosis (7.3%), stroke (7.3%) and portal hypertension (2.4%). All these cases were presented with a Hct more than 50%. Similarly, Berk et al. ^[25] reported that risk of thrombosis is more if the Hct is above 50%.

With a median 6 number of therapeutic phlebotomies, aspirin & Hydroxyurea in polycythaemia vera, 30 (73.1%) cases attended the target Hct level. But there was again elevation in the Hct level in 9 (21.9%) cases of PV after attaining the target level. 11(26.8%) cases did not yet attain the target Hct level 45 %. This finding was similar to the studies of Thomas et al.^[26] and Washerman & Gilbert. ^[27]

The progression of the polycythaemia vera to thrombosis was found in 17% cases which was similar to Najean & Rain et al., ^[28] but more than that of Berk et al.(4%). ^[25] Myelofibrosis was found in 5% cases which is similar to Berk et al. ^[25] but lesser than Najean & Rain et al (17%) and Lawrence JH et al (25%). ^[29] MPN was detected in 5% cases which is similar to Najean & Rain et al. ^[28]

Conclusion

Therapeutic phlebotomy is a cost effective and safe treatment for patients having high haematocrit. It also prevents life threating complications by maintaining target haematocrit. Only disadvantage is having milder variety of adverse reactions and development of iron deficiency after multiple procedures. Also, in patients who are presenting with stroke, it cannot decrease the haematocrit suddenly to a target level, as only a small amount of blood can be removed in one procedure. So, in such cases the use of advanced technology like erythrocytapheresis, which can remove larger amount of blood and achieve target haematocrit within a short period of time should be introduced. Only disadvantage of erythrocytapheresis is the cost. Newer technique like hematopoietic stem cell transplant can be used for complete response in PV cases.

However, it is important to make treatment decisions based on each patient’s condition and the relevant guidelines for prescribing and implementing phlebotomy. Furthermore, we recommend prioritizing the creation of treatment guidelines with staff and patient education programs for institutions that are seeking to introduce phlebotomy programs. These guidelines should also focus on patient care after the completion of the phlebotomy. In conclusion, the evidence that we have observed, indicates that phlebotomy is safe and provides good efficacy with relatively low costs, so it should be the first line of treatment in the above cases as cytoreductive therapy has serious adverse effects and further studies are needed to improve the treatment guidelines for phlebotomy.

Limitation

Three cases could not be traced due to their remote location. Due to economic hindrance, four numbers of cases could not be investigated for JAK2 mutation. Consent could not be obtained in two numbers of PV cases for bone marrow study due to their reluctance. Due to lack of infrastructure, patients with stroke could not be subjected to erythrocytapheresis procedure.

Conflict of Interest

None.

Source of Funding

None.