Trigger factors for prophylactic platelet transfusion

Blood Reviews (1998) 12,23&238 0 1998 Harcourt Brace & Co. Ltd

Consensusconferenceon platelet transfusion

Trigger factors for prophylactic platelet transfusion

P. J. Ancliff, S. J. Machin The level of 20x109/Lfor prophylactic platelet transfusion has rightly been challenged over the last few years,with some units recommending a level as low as 5x109/L.The higher levels are usually based on retrospective data from the 1950s.We examined the more recent data and came to the conclusion that a threshold of 10x109/Lis safe in the stable patient; higher levels are recommended for specific clinical circumstances. This threshold will reduce donor exposure,costs and possibly donor alloimmunization. The dearth of prospective controlled clinical trials in the literature also presentsan opportunity for both in-house and national audit. INTRODUCTION

(alloimmunization is covered by a separate presentation and will not be discussed further here). The number of available donations is also limited and the cost (currently around &200 per ‘adult pool’) is not insignificant.

Effective platelet concentrates first became available towards the end of the 1950s. Since this time the quantity used, primarily for prophylaxis has increased dramatically.’ The North London Blood Transfusion Centre serves a population of around 3.5 million and in 1994 processed 155 000 units, compared to 75 000 in 1985 and 30 000 in 1975. The use of prophylactic platelets has undoubtedly improved survival for leukaemia patients, in particular by allowing the use of more intensive combination chemotherapy regimes associated with prolonged bone marrow aplasia. The trend looks set to continue with the increasing use of high dose chemotherapy in conjunction with peripheral blood stem cell rescue for solid tumours, most notably breast cancer. National guidelines2 on platelet usage have previously been published but did not define a threshold for prophylactic transfusion. We aim to address this issue, to ensure that patients receive adequate supportive therapy yet are not exposed to unnecessary risk of infection or possible alloimmunization,

P.J. Ancliff, S.J. Machin, College Hospital, Grafton Correspondence

Department of Haematology, Way, London WClE 6DB,

HISTORY Until the present decade the policy of prophylactic transfusion at a count of 20 x 109/L was widely practised and accepted. However, the original data on which this assumption was believed to be based does not support this threshold. The landmark paper was published by Gaydo$ et al in 1962. This retrospective analysis of 92 newly diagnosed acute leukaemic patients treated at the end of the 1950s demonstrated a quantitative relationship between platelet count and significant haemorrhage (Fig. 1). However, in this study there was no suggestion of a threshold and the authors even commented that ‘This type of relation (sic) does not exist between platelet count and haemorrhage.’ In addition, the effect of aspirin (widely used as both an anti-pyretic and analgesic) on haemostasis was not fully appreciated until later in that decade.“s5 Most haematology patients would have received aspirin since it was freely used as both an anti-pyretic

University UK

to: P.J. Ancliff

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Fig. 1 Percentage of days with grossly visible haemorrhage (haematuria, melena and haematemesis) against platelet count category. No clear threshold is seen. (Gaydos et a1.j with permission)

Fig. 2 Stool blood loss versus platelet count in 20 aplastic patients. Curve redrawn using original data from Slichter and Harker,6 (with permission). there is suggestion of a threshold between 5 and lOxlO’/L.

and analgesic agent. Much later work,6 when aspirin was no longer given to thrombocytopenic patients (Fig. 2), did indeed suggest a threshold, albeit at a level of between 5 and 10x109/L. In 1966, Freireich’ selected a threshold of 20x109/L having observed that haemorrhage occurred on 16% of days when platelet counts were between 20 and 50x109/L but on 92% of days when the count was less than 1xlOYL. In 1974 Higby et al8 selected a level of 30x109/L citing the original Gaydos paper as justification. However, their study added little. All haemorrhages occurred with a platelet count below 5x109/L and there was no significant difference between the counts of the prophylaxed and non-prophylaxed arms. Murphy et aP” studied 90 children using a prophylactic threshold of 20x109/L. A reduction in bleeding was observed early in the treatment, but an increased amount was noted later on. Survival was unaffected. All of these early studies demonstrated a trend towards reduced bleeding with prophylactic platelets, but none of them truly addressed the issue of a threshold. A prophylactic level of 20x109/L merely became incorporated into standard practice.

Also in 1978 in a letter to the Lancet, Solomon” et al published preliminary findings of a randomized study comparing prophylaxis (giving platelet transfusions whenever the count was below 20x109/L) with specific indication transfusion (clinically significant bleeding or a count of < 20x109/L which was preceded by a decline of > = 50% in the platelet count over the previous 24 h). The results re summarized in Table 1. As can be seen, although the numbers are fairly small the ‘specific indications’ group required around half the number of platelet transfusions and fared just as well. Ironically, the only haemorrhagic deaths occurred in the ‘prophylaxis’ arm, two died on the first day (and were therefore excluded) and two died during treatment. There were no haemorrhagic deaths in the ‘specific-indications’ group. Sadly, Solomon died shortly after this letter was published and no further reports were submitted. Further, opinions’” were voiced that the threshold could be safely lowered, although the conclusion of the US National Institute of Health Consensus ConferenceI in 1987 was rather meek, referring to the 20x109/L threshold: ‘Recent evidence suggests that, based on clinical judgement and close observation, this number might be safely lower for some patients.’

AFTER ASPIRIN CHANGES

Slichter and Harke? in 1978 produced the first good evidence of a threshold, however, at a much lower level than previously practised (Fig. 2). They assessed stool blood loss in 20 aplastic thrombocytopenic patients. Blood loss was less than 5 ml per day with a platelet count of greater than 10x109/L. At levels of 5-10x109/L, blood loss was 9 +/- 7 ml/day and below 5x109/L markedly elevated at 50 +/- 20 ml/day.

IN THE 1990s

With the increased understanding of the causes of bleeding in thrombocytopenia, general opinion is now coming around to the idea that in many circumstances, the platelet transfusion threshold can be considerably lower than 20x109/L, possibly even as low as 5x109/L. This latter assumption is based on a good prospective study by Gmur et a1.14In a very stringent

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1 Data from Solomon1 1 (with permission). The prophylactic group were transfused when the count was below 20x109/L, the ‘specific indications’ group only received transfusion for significant bleeding and a count of <20x109/L preceded by a fall of > = 50% over the preceding 24 h. There were no excessdeaths in the ‘specific indication’ arm

Table

Prophylactic

Patient group

Age (year) (mean + SE) Platelet packs per course (mean + SE) Red cell packs per course (mean f SE) Complete remissions Complete and partial remissions All deaths within 1 month/course Bleeding deaths within 1 month/course

n = 22

Specific indications n= 17

45 * 3* 31.9 * 5.9 6.7 i 1.0 9117 14117 3122 2122

44+5* 16.1 ‘r 3.4 7.3 + 1.0 6112 10/12 2117 o/17

*One patient excluded because granulocyte transfusions were given. Table 2 Platelet transfusion protocol for the Gmur study Morning platelet count (x 109/L)

Prophylactic platelet transfusion on the same day indicated

O-5 6-10

In every case In the presence of fresh minor haemorrhagic manifestations; body temperature < 38°C In the presence of coagulation disorders and/or heparin therapy; before bone marrow biopsy or lumbar puncture In the presence and until control of major bleeding complications; before minor surgical procedures

1 l-20 >20

study (which one can argue is not totally applicable to everyday practice) 102 acute leukaemia patients were transfused according to the criteria in Table 2. When the platelet count was below 50x109/L, the patients were examined daily (including fundoscopy) for signs of haemorrhage. Such counts were also checked manually (and this value used). If the manual and automated counts differed by more than 20%, the manual count was further repeated. Minor bleeding episodes included any mucocutaneous haemorrhage or haematomas not requiring red cell transfusion, as well as retinal haemorrhages without impairment of vision. Major bleeding included melena, haematemesis, haematuria and haemoptysis whether or not red cell transfusion was required and epistaxis, vaginal or soft-tissue bleeding where such transfusion was necessary. Fresh retinal haemorrhage with impairment of vision also constituted a major bleeding episode. Figure 3 shows the computed risk of bleeding against platelet count. Thirty-one major bleeding episodes occurred on 1.9% of the study days when platelet counts were 10x109/L or less and only on 0.07% of days with counts of lo-20 x109/L. Of the 31 major bleeds, three were fatal - two had disseminated intravascular coagulation (DIC) and had lowest recorded counts of 53 and 8x109/L. The third died from a subdural haematoma with a count of less than 1x109/L due to refractoriness and lack of an HLA

identical donor, Of the remainder epistaxis requiring red cell support and tamponade occurred four times. Three episodes of haemoptysis, seven of gastrointestinal haemorrhage and three of macrohaematuria were observed. Six of these cases required red cell support. The remaining 11 major events were retinal haemorrhage with visual loss. All bar one of these recovered completely. The exception was left with vitreous body formation and permanent visual impairment, but did have DIC and was receiving heparin at the time of injury (platelet count at the time SxlO’/L). The authors conclude that ‘the threshold for prophylactic transfusion can safely be set at 5xlOVL in patients without fever or bleeding manifestations and at 10x109/L in patients with such signs’. They attribute the low rate of refractoriness (10%) observed in their study to the use of single-donor products rather than reduced numbers of units. Murphy” wondered whether the threshold would be better set at 10x109/L in view of the major haemorrhages occurring in the 6-10x109/L group. GmuP disagreed, noting that the risk of major haemorrhage was only 1.5% (10 cases in 687 days) in this group and that although they all occurred in the non-transfused group (10 episodes in 229 days, i.e. 4.4%) only one required urgent transfusion and only one suffered long-term sequelae (the retinal haemorrhage associated with DIC described above). Gmur conceded that although a threshold of

Trigger factors for prophylatic platelet transfusion

10~1O’/L would not have increased the transfusion requirements by much, he felt the data did not support this increase. We are, therefore, left with two concerns about a threshold of 5x10y/L: o Are manual platelet counting and daily fundoscopy practical and reliable for day to day practice? l Is the apparent 4.4% risk of major haemorrhage in the stable patient with a count of 6-10x109/L acceptable? Unfortunately, from the published data the risk of haemorrhage with a count of 1I-15x10y/L cannot be determined precisely yet from Figure 3 we can see that this must be very low. Kelsey’j audited the use of platelet concentrates in a busy London teaching hospital both before and after the introduction of a new lower threshold of 15x109/L. Major haemorrhage was defined similarly to Gmur and was 12% in the initial audit (71 patients, 82 thrombocytopenic episodes with 38% having acute leukaemia, 55% a diagnosis of lymphoma and the remainder multiple myeloma or aplastic anaemia). Treatment comprised 40 autografts, 3 allografts and 39 episodes of conventional chemotherapy. When the threshold was lowered to 15x109/L (from 20x109/L), the risk of major haemorrhage was essentially unchanged at 10% (70 patients - diagnosis and treatment not specified). Of the 36 patients in the published data, they required on average two less platelet transfusions per thrombocytopenic period. In 1993, based on the data of Slichter and Harker and Gmur, BeutleP suggested a threshold of 5x10y/L for the stable patient. He concluded that although the patient may bleed and the physician be blamed, should the physician also not be worried about the unnecessary transfusion that may cause harm? Also on the above data, Hussein and Hoeltge” (1996) suggest a threshold of 10x109/L, citing Gmur’s paper as their justification. It is not clear why they chose 10 rather than 5x109/L. They do, however, treat their threshold differently in that platelets are administered if serial daily counts suggest the NEXT day’s count will be below lOxlO’/L. If this is difficult to predict, the count is repeated 8 to 12 h later and the decision made then, a not entirely practical arrangement considering that most departments need to order the day’s products shortly after noon from the regional transfusion centres. Two important randomized clinical trials have added further weight to the argument for a reduced threshold. Heckman** compared a threshold of 10 to 20x109/L in 78 patients undergoing induction therapy

237

r

Risk category

by platelet

count (x 1OV)

Fig. 3 Relation of bleeding risk to blood platelet counts: computed per 1000 days at risk. Open bars = minor bleeding complications. Solid bars = major bleeding complications. n = numbers of observed days at risk in a given class during the trial. The correlation coefficient between the first four classesand risk of bleeding is I’ = 0.963, P < 0.01. Risk category platelets > 20 was excluded. (Gmur et al.” with permission.)

for acute leukaemia. The total number of platelet transfusions were 11 and 7 in the higher and lower arms respectively. This approached statistical significance (P = 0.07). There were no deaths from haemorrhage in either arm and no significant effects on morbidity, The Italian GIMEMA groupz3 recently reported a multi-centre randomized study of 255 patients receiving induction therapy for acute myeloid leukaemia using similar thresholds. There was only one haemorrhagic death (in the restrictive arm) although at the time of haemorrhage the patient had a count of 32x109/L. The authors report that lowering the threshold reduced platelet usage by 21.5% However, the authors admit that the proportion of days of hospitalization with major haemorrhage was increased from 2 to 3.1%. They state that they are unaware of the clinical significance of this result. Rather unfortunately, there was an excess of deaths (primarily infective) in the lower threshold arm group (13.3% versus 7.5%) and the authors make no comment on this difficult to explain finding.

CONCLUSIONS

AND RECOMMENDATIONS

It is clear that a prophylactic platelet threshold of 20x109/L is no longer justifiable. Improvements in supportive care have been dramatic since the late 19.50s. Therefore, we recommend halving the threshold to 10x109/L in stable patients. Although Gmur proposed a level of 5x109/L, the small additional numbers of transfusions necessary to achieve a threshold of 10x109/L are probably justified in view of the small, but significant, numbers of major haemorrhages

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which occurred in the 6-10x109/L treatment group. This will undoubtedly reduce donor exposure and costs and may also reduce donor alloimmunization. Clearly, when introducing a lower threshold for routine clinical practice, it is essential that all patients have a daily clinically examination by experienced medical staff. To achieve significant statistical power, proof of the above threshold would require a large multi-centre study as the incidence of major haemorrhage in the non-refractory patient is thankfully now small. Furthermore, to rely on a specific platelet count, such as 10x109/L for prophylactic transfusions in the asymptomatic patient, one has to be aware of the accuracy and precision of the laboratory automated blood cell counter. Reliance on a manual count in the modern laboratory at this level is completely inappropriate with CVs ranging up to 20% and is also not a practical option with reduced staff numbers. Most automated cell counters rely on the impedance principle and therefore tend to slightly overcount at low levels (< 10x 109/L) due to the false counting of non-platelet particles. An optical platelet count using light scattering measurement in a laser flow chamber of an immunological count (using platelet specific monoclonal antibodies, i.e. CD41, 42 or 61) and flow cytometry may fully resolve platelets, improving further the precision and accuracy of platelet counting.”

30x109/L would seem appropriate, whereas for tunnelled catheters and minor surgical procedures we recommend a level of 50 x 1OYL. In patients with active bleeding (excluding nosebleeds and modest menstrual loss) it is common practice to aim for a count of 50x109/L initially. Once the bleeding has settled, the threshold can be lowered to 30x109/L for 3-4 days. For all major surgery our target would be 80x109/L, although some*O have argued for a level as low as 20x109/L being safe in abdominal surgery. REFERENCES

4. 5. 6 I 8 9 10.

SPECIFIC

THRESHOLDS

This is probably best divided into two sections, stable patients and specific indications. The first recommendation is based on well conducted clinical studies and would therefore attract a grade B. The remainder are merely based on current practice and opinion and therefore only merit a C. In stable, amegakaryocytic patients we recommend only transfusing prophylactically if the platelet count is below 10x109/L. This includes patients with temperatures of > 38°C but of course clinical judgement must prevail in the seriously septic patient. In the presence of significant coagulation disorders or heparin therapy, transfusion should be performed with a threshold of 20x109/L. A similar level of above 20x109/L should be chosen for lumbar puncture and bone marrow trephine (an aspirate can be safely performed at lower levels). Ideally, one should perform a 1 h increment if additional platelets are necessary. However, in the refractory (or heavily consumptive) patient, the procedure should be performed immediately after the infusion. For the insertion of nontunnelled central venous access catheters a level of

11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

23.

Machin et al. Platelet transfusion. Thromb Haemost 1995; 74(l): 246. BCSH. Guidelines for platelet transfusion. Transfus Med 1992; 2: 311. Gaydos LA, Freireich EJ, Mantel N. The quantitative relation between platelet count and haemorrhage in patients with acute leukaemia. N Eng J Med 1962; 266: 905. Quick AJ. Salicylates and bleeding: the aspirin tolerance test. Am J Med Sci 1966; 252: 2265. O’Brien JR. Cell membrane damage, platelet stickiness and some effects of aspirin. Br J Haematol 1969; 17: 610. Slichter SJ, Harker LA. Thrombocytopenia: mechanisms and management of defects in platelet function. Clin Haematol 1978; 7: 523. Freireich EJ. Effectiveness of platelet transfusion in leukaemia and aplastic anaemia. Transfusion 1966; 6: 50. Higby DJ et al. The prophylactic treatment of thrombocytopenic leukaemic patients with platelets: a double blind study. Transfusion 1966; 6: 50. Murphy S, Kock PA, Evans AE. Randomised trial of prophylactic vs therapeutic platelet transfusion in childhood acute leukaemia. Clin Res 1976; 24: 379A. Murphy S et al. Indications for platelet transfusion in children with acute leukaemia. Am J Haematol 1982; 12: 347. Solomon J et al. Platelet prophylaxis in acute nonlymphoblastic leukaemia. Lancet 1978; I: 267. Beutler E. An iconoclastic view of conventional wisdoms in haematology. Arch Intern Med 1979; 139: 221. Platelet transfusion therapy. JAMA 1987; 257: 1777. Gmur J et al: Safety of a stringent prophylactic platelet transfusion policy for patients with acute leukaemia. Lancet 1991; 338: 1223. Murphy WG. Prophylactic platelet transfusion in acute leukaemia. Lancet 1992; 339: 120. Gmur J. Prophylactic platelet transfusion in acute leukaemia. Lancet 1992; 339: 120. Kelsey HC. An audit of the use of platelet concentrates in the prophylaxis of thrombocytopenic haemorrhage in a large haematology unit. Blood Coag & Fibrinolysis 1992; 3: 647. Beutler E. Platelet transfusions: the 20,000/@ Trigger. Blood 1993; 81: 1411. Hussein M, Hoeltge G. Platelet transfusion therapy for medical and surgical patients. Cleveland Clin J Med 1996; 63: 245. Bishop JF et al. Surgery in Acute leukaemia. A review of 167 operations in thrombocytopenic patients. AM J Haematol 1987; 26: 147. Ault KA. Platelet counting: is there room for improvement? Laboratory Haematology 1996; 2: 139. Heckman KD et al. Randomised study of prophylactic platelet transfusion threshold during induction therapy for adult acute leukaemia: lO,OOO/microL versus 20.000/microL. J clin Oncol 1997; 15(3): 1143 Rebulla P et al. Threshold for prophylactic platelet transfusions in adults with acute myeloid leukaemia. N Eng J Med 1997; 337: 1870.