Retrospective evaluation of the indications,safety and effects of fresh frozen plasma transfusions in 36 cats (2014

Abstract

Objectives

The goals of this study were to classify the indications, risks, effects on coagulation times and outcomes of cats receiving fresh frozen plasma (FFP) transfusions in clinical practice.

Methods

This was a retrospective study of FFP transfusions administered in two referral hospitals from 2014 to 2018. Transfusion administration forms and medical records were reviewed. Information was collected on indication, underlying condition, coagulation times and signs of transfusion reactions. Seven-day outcomes after FFP administration were also evaluated when available.

Results

Thirty-six cats received 54 FFP transfusions. Ninety-four percent of cats were administered FFP for treatment of a coagulopathy. Twenty cats had paired coagulation testing before and after FFP administration. Eighteen of these cats had improved coagulation times after receiving 1–3 units of FFP. Eight of the 36 cats had probable transfusion reactions (14.8% of 54 FFP transfusions). These reactions included respiratory signs (n = 4), fever (n = 2) and gastrointestinal signs (n = 2). Five of the eight cats with probable reactions had received packed red blood cells contemporaneously. Overall mortality rate during hospitalization was 29.7%, with 52.8% (n = 19/36) of cats confirmed to be alive 7 days after discharge.

Conclusions and relevance

This retrospective study shows that FFP transfusions improve coagulation times in cats. Transfusion reactions are a risk, and risk–benefit ratios must be measured prior to administration and possible reactions monitored. In the study cats, the FFP transfusions appeared to be a tolerable risk given the benefit to prolonged coagulation times.

Keywords

Fresh frozen plasma FFP transfusion reaction coagulopathy coagulation times

Introduction

Blood transfusions can be life-saving but also carry a risk of adverse events. While the use of component blood therapy has decreased the risk of transfusion reactions,^1,2 the risk–benefit ratio should be assessed prior to administration. Fresh frozen plasma (FFP) transfusions have been widely used in both human and veterinary medicine, although some indications for administration have changed and continue to evolve.^3–5 Initially, plasma transfusions were administered for coagulopathies, hypoproteinemia^6–9 and, in some cases, for severe pancreatitis.^10,11 Current recommendations for plasma transfusions in people include trauma patients who require massive transfusion and patients with coagulopathy and active bleeding, particularly intracranial hemorrhage.^12,13 More recently in veterinary medicine, plasma transfusions have been prescribed primarily for coagulopathies (inherited and acquired), both therapeutically to treat clinical signs of bleeding, and prophylactically to prevent bleeding prior to invasive procedures.^4,5 However, recent medical research has shown that there is little difference in bleeding complications in patients with a coagulopathy, regardless of administration of prophylactic FFP.^14,15 These studies have suggested that plasma may be over-prescribed.^16–18

Potential complications associated with blood component transfusions include immune reactions such as anaphylaxis, fever (with or without hemolysis), pruritus, acute gastrointestinal (GI) signs, systemic inflammatory response syndrome and transfusion-related acute lung injury (TRALI), as well as non-immune reactions such as transfusion-associated cardiac overload and transmission of infectious diseases.^2,11,19,20 In humans, the most common reactions to plasma specifically are allergic reactions and fever.²¹ TRALI is less common but is the most common cause of transfusion-related mortality for any blood product, and occurs mostly in critically ill patients.¹⁹ In one large study of 558 dogs, transfusion reactions were reported in 8% of plasma transfusions, with fever being the most common reaction. This is lower than the reported transfusion reactions of 22% when packed red blood cells (pRBCs) were transfused and 17% when pRBCs and plasma were administered simultaneously in the same study.¹ There is limited information about reactions to plasma in cats. In one retrospective study, no reactions were reported in 19 FFP transfusions in 13 cats.⁶ In another study of 283 dogs and 25 cats administered FFP, only three reactions were reported and it is unclear if they were in the dogs or the cats.⁵

The purpose of this retrospective study was to assess more carefully the use of FFP transfusions in clinical practice, potential transfusion reactions, effects on laboratory testing of coagulation (prothrombin time [PT] and activated partial thromboplastin time [aPTT]), as well as outcomes in cats. Owing to the nature of retrospective studies, assessment of clinical hemorrhage in these patients could not be determined.

Materials and methods

Data collection

All transfusion events and associated patient medical records involving FFP in cats at two Veterinary Emergency and Critical Care Society-certified level I emergency and critical care facilities (BluePearl – North Seattle, and BluePearl – Renton) from 1 January 2014 to 31 December 2018 were reviewed. Information collected included body weight, stated reason for transfusion, final diagnosis (if known), history of prior transfusions, administration of medication during transfusion, vital signs during and after the transfusion, packed cell volume (PCV), total solids (TS), PT and/or aPTT performed by in-house analysis (IDEXX Coag Dx Analyzer; IDEXX Laboratories) prior to and after transfusion, survival to hospital discharge and 7-day outcomes. Change in coagulation times pre- and post-FFP transfusion were calculated when available. If PT and aPTT values were out of the detectable range, the highest value that could be measured was used for purposes of calculating improvement in coagulation times. Records were reviewed carefully for any sign of acute transfusion reaction using the criteria listed below.

A transfusion was defined as administration of an individual unit to a patient from a donor. Cats may have received multiple transfusions during hospitalization. All FFP recipients were blood-typed using a chromatographic in-house kit for type A, type B or type AB (Alvedia Quick Test Blood Typing Feline; Alice Veterinary Diagnostic). All FFP units administered were by donors of the same blood type as the recipient. Minor crossmatches were not performed. Some cats were provided pRBCs or whole blood (WB) in addition to FFP. Major crossmatches were performed for all of these cases using an in-house crossmatch test (RapidVet-H Companion Animal Crossmatch Test; DMS Laboratories).

Blood donor screening, unit preparation and storage

All FFP units were produced from community blood donor cats by the BluePearl Blood Bank in Seattle. Blood donor cats were typed for type A, type B and type AB, and were indoor-only cats. Screening was performed on all cats in accordance with the American College of Veterinary Internal Medicine consensus on screening for feline blood donors.²² A full physical examination by a veterinarian was also performed prior to each donation. Most cats donated blood with brief anesthesia. Blood collection, separation into components and storage protocol was adapted from a previous publication.²³

Plasma administration

All FFP transfusions were administered with a syringe, infusion pump (Infusion Pump Model AS50; Baxter International) and filter (Hemo-nate Filter Disposable 18 Micron Blood Filter; Utah Medical Products). Gener-ally, transfusions were administered intravenously at 1 ml/kg/h for the first 15 mins, then 5 ml/kg/h for the next 15 mins, followed by a rate adequate to deliver the transfusion within 4 h unless the clinician prescribed a shorter administration time. Full vital signs (temperature, heart rate, respiratory rate, mucous membrane color, capillary refill time and blood pressure) were recorded every 15 mins for the first hour then hourly thereafter during transfusion using a standard transfusion sheet (Figure 1). Vital signs were repeated within 8 h of completion of transfusion. Cats were not routinely prescribed diphenhydramine or corticosteroids. Other medications were not administered during the transfusion unless deemed necessary by the attending clinician.

Figure 1

Transfusion administration form

Transfusion reaction definitions, imputability and grading

Criteria for definition of transfusion reactions and imputability were modified from the National Healthcare Safety Network²⁴ and from a 2017 study on acute transfusion complications in dogs.²⁵ Grading the severity of reactions was adapted from the Veterinary Cooperative Oncology Group (VCOG) consensus²⁶ and applicable definitions compiled in Table 1.

Table 1

Grading of transfusion reactions*

	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Respiratory: pulmonary edema	Radiologic findings only: minimal dyspnea on exertion	Moderate dyspnea on exertion; medical intervention indicated	Severe dyspnea or dyspnea at rest; oxygen indicated	Life-threatening respiratory compromise; urgent intervention or intubation with ventilatory support indicated	Death
Respiratory: tachypnea (not panting)	Respiratory rate up to 60 bpm	>60 bpm; increased abdominal effort	Oxygen indicated	Life-threatening; ventilatory support indicated	Death
Fever	39.5–40.0°C (103.5–104°F)	>40.0–41°C (>104– 105.8°F), transient (<6 h); not requiring hospitalization	>41–42°C (>105.8– 107.6°F), prolonged (>6 h); requiring hospitalization	>42°C (>107.6°F)	Death
GI: nausea/ ptyalism	Loss of appetite without an alteration in eating habits	Salivation or ‘smacking of lips’ <3 days, grade 2 anorexia	Salivation or ‘smacking of lips’ >3–5 days, grade 3 anorexia	Salivation or ‘smacking of lips’ >5 days, grade 4 anorexia	–
GI: vomiting	<3 episodes in 24 h, medical intervention not indicated	3–10 episodes in 24 h; <5 episodes/ day for 48 h; parenteral fluids (IV or SC) indicated 48 h; medications indicated	Multiple episodes >48 h and IV fluids or PPN/TPN indicated >48 h	Life-threatening (eg, hemodynamic collapse)	Death

GI = gastrointestinal; bpm = breaths per minute; IV = intravenous; SC = subcutaneous; PPN = partial parenteral nutrition; TPN = total parenteral nutrition

Adapted from the Veterinary Cooperative Oncology Group consensus²⁶

Allergic/anaphylaxis reactions were defined as the development of pruritus, facial swelling, erythema, urticaria or vasodilatory shock during or within 4 h of the end of the transfusion. Fever was defined as an increase in rectal temperature >1°C (1.8°F) from baseline in a previously normothermic or hyperthermic patient, during or within 4 h of the end of the transfusion. Subjects that were hypothermic at the beginning of the transfusion were allowed to have an increase of more than 1°C (1.8°F) without classification of a fever as long as the body temperature did not increase above 39.2°C (102.5°F). Transfusion-related hemolysis was defined as development of hemolyzed serum or new hemoglobinuria if not previously documented. Serum color was routinely noted on PCV/TS performed prior to and after transfusion. Respiratory events were defined as changes in a patient’s respiratory rate and character above normal parameters, with or without the need for oxygen supplementation or other medications, during or within 4 h of the end of the transfusion. GI events were defined as regurgitation, ptyalism, vomiting or diarrhea that was new or worsened during or within 4 h of the end of the transfusion. Neurologic signs were defined as changes in mentation, gait, proprioception or specific nerve deficits identified by clinician examination during or within 4 h of the end of the transfusion. Death owing to a transfusion-related complication was defined as cardiac arrest during or within 4 h of the end of the transfusion not explained by another reason.

Reactions were characterized as definitively, probably or possibly caused by the transfusion. Definitive reactions were those where the patient had no other conditions that could explain the clinical signs. In probable reactions, there were other causes present that could explain the signs, but the transfusion was most likely. In possible reactions, other causes were more likely, but the transfusion could not be ruled out.²⁴

Results

Thirty-six cats received 54 FFP transfusions. One cat with known hemophilia B received FFP transfusions twice in a 13-month period for two different indications and survived both hospitalizations. Clinicians cited three indications for FFP transfusions in the study cats: (1) coagulopathy prior to invasive procedures (n = 19/37); (2) coagulopathy without invasive procedures (n = 16/37); and (3) hypoalbuminemia (n = 2/37). The presumptive or confirmed diagnosis and outcomes for each category are summarized in Table 2.

Table 2

Presumptive diagnoses and outcomes of fresh frozen plasma-transfused cats

Presumptive diagnosis	Number of cats with diagnosis (n = 36)	Number of cats that survived to discharge	Number of cats that survived 7 dayspost-discharge
Hepatopathy (non-neoplastic)	10 (27.8)	10/10 (100)	7/10 (70)
Neoplasia (hepatic, GI, MCT)	7 (19.4)	5/7 (71.4)	2/7 (28.6)
Septic abdomen (suspected or confirmed)	6 (16.7)	2/6 (33.3)	2/6 (33.3)
Suspected anticoagulant rodenticide toxicity	5 (13.9)	5/5 (100)	4/4 (100)*
Hemophilia B	1 (2.8)	1/1 (100)	1/1 (100)^†
Diabetic ketoacidosis	1 (2.8)	1/1 (100)	1/1 (100)
Heat stroke	1 (2.8)	0/1 (0)	0/1 (0)
Trauma	1 (2.8)	0/1 (0)	0/1 (0)
Unknown/other	4 (11.1)	1/4 (25)	1/4 (25)

Data are n (%)

One cat with unknown 7-day outcome

†

This cat was hospitalized two different times and survived 7 days after both discharges

GI = gastrointestinal; MCT = mast cell tumor

Eighty-nine percent of cats (n = 32/36) were type A and 11% (n = 4/36) were type B. There were no type AB cats. Twenty-two cases received a single unit of FFP (median 5.87 ml/kg; range 2.15–10.16 ml/kg), 13 cases received two units of FFP (median 9.40 ml/kg; range 6.81–19.80 ml/kg) and two cases received three units of FFP (median 10.63 ml/kg; range 9.27–11.99 ml/kg). All cases of multiple FFP transfusions were performed within a 24-h period either due to clinician assessmentor continued documented coagulopathy. The median volume of FFP transfused per case was 6.81 ml/kg (range 2.15–19.8 ml/kg).

Coagulation testing and correction

Coagulation testing was available in 33/36 cats (92%). Ninety-seven percent of those tested had prolonged PT and/or aPTT. Paired coagulation testing before and after FFP administration was performed in 20 cats (Table 3). Ten of these 20 cats had signs of active bleeding (petechiae, bruising, hemoabdomen and/or GI bleeding). Coagulation times were rechecked a median of 2.75 h after the completion of the FFP transfusion (range 0–20 h). Coagulation times were improved in 18/20 cats after 1–3 units of plasma. The median change in PT per unit FFP transfused was –27.5 s. The median change in aPTT per unit FFP transfused was –80 s.

Table 3

Coagulation times before and after fresh frozen plasma (FFP) transfusion

Diagnosis (case number)	Pre-transfusion PT (s)	Post-transfusion PT (s)	Change in PT (s)	Pre-transfusion aPTT (s)	Post-transfusion aPTT (s)	Change in aPTT (s)	FFP dose (ml/kg)
Hepatopathy (non-neoplastic)
1	100	19	−81	300			6.35
2	38	100	62				4.55
3	33	24	−9	133			5.59
4	100	33	−67	194	117	−77	7.39
Septic abdomen
5	100	15	−85	237	95	−142	19.80
6	44	22	−22	198			5.35
7	31	23	−8	140	124	−16	6.58
8a*	100	26	−74	187	144	−43	6.00
8b*	35	14	−21	131	87	−44	4.85 (10.85 total)
9	87	25	−62	212	129	−83	7.14
Suspected anticoagulant rodenticide
10a*	100	28	−72	300	144	−156	4.00
10b*	28	28	0	144	100	−44	4.00 (8.00 total)
10c*	44	23	−21	111			3.99 (11.99 total)
11	100	29	−71	300	112	−188	4.04
12a*	100	100	0	300	300	0	5.38
12b*	100	21	−79	300	127	−173	5.33 (10.71 total)
Neoplasia
13	100	22	−78	300	135	−165	2.15
14	37	16	−21	300	53	−247	4.74
15	43	16	−27	212			9.09
16	100	72	−28	34			5.36
17	24	26	2	300	46	−254	5.94
Unknown/other
18	100	100	0	300			4.17
19	29	21	−8	128	102	−26	3.68
DKA
20	100	35	−65	300	127	−173	7.94

Reference interval for prothrombin time (PT) is 15–23 s. Reference interval for activated partial thromboplastin time (aPTT) is 70–120 s

Denotes multiple transfusions in the same patient

DKA = diabetic ketoacidosis

Transfusion reactions and 7-day outcomes

Eight of the 36 cats had probable transfusion reactions (14.8% of 54 FFP transfusions). Only 1/54 transfusions was discontinued by the attending clinician. Potential transfusion reactions were reviewed retrospectively by all three authors. No reactions could be definitely assigned to the transfusion. However, we were in consensus that eight reactions were considered probable and worthy of discussion. Many of the cats in this study received additional blood products concurrently, defined for these purposes as within 8 h of FFP administration. Of the 37 cases, 20 received FFP alone (31/54 transfusions), 15 cases received pRBCs concurrently (20/54 transfusions) and two cases received WB concurrently (3/54 transfusions). Of the eight probably reacting cats, three received FFP alone and five also received pRBCs (Table 4). Owing to the product administration timing, it could not be distinguished which blood product caused the probable transfusion reaction.

Table 4

Probable transfusion reactions and grade(s)* by blood product type(s) in 54 transfusion events

Type of reaction	FFP alone(n = 31)	Reaction severity grade:FFP alone	FFP + pRBC(n = 20)	Reaction severity grade(s): FFP + pRBC	FFP + WB(n = 3)	Total reactions (n = 54)
Respiratory	1 (3.2)	3	3 (15.0)	2, 3, 4	0	4 (7.4)
Fever	1 (3.2)	2	1 (5.0)	1	0	2 (3.7)
Gastrointestinal	1 (3.2)	2	1 (5.0)	1	0	2 (3.7)
Allergic	0		0		0	0
Hemolysis	0		0		0	0
Hypotension	0		0		0	0
Neurologic	0		0		0	0
Cardiac arrest/death	0		0		0	0
Total transfusions	3 (9.7)		5 (25.0)		0/3 (0%)	8 (14.8)

Data are n (%)

See Table 1 for definitions of grades

FFP = fresh frozen plasma; pRBC = packed red blood cells; WB = whole blood

Other

No cats developed new signs of hemolysis, hypotension or neurologic deficits within 4 h of transfusion. No cats suffered cardiac arrest during FFP transfusion but three cats (9.4%) died or were euthanized within 4 h of the FFP transfusion. All three of these cats were unstable prior to starting the transfusion and their death was not thought to be related to the transfusion.

Overall mortality rate during hospitalization was 29.7% (n = 11/37) with the remainder discharged. Of the 26 cases that were discharged, 19 were confirmed to be alive 7 days later; one cat was lost to follow-up. Of the eight cats with transfusion reactions, only 2/8 cats were alive 7 days after discharge.

Discussion

This study provides a detailed look at clinical use, potential transfusion reactions, effects on coagulation times and survival outcomes for cats receiving FFP. In contrast to the 54 FFP transfusions administered in the two hospitals, 474 pRBC and 76 WB transfusions were administered to cats during the same 5-year period. On account of the relative infrequency of FFP transfusions in cats, the number of cases is low. A prospective multicenter study should be considered to increase FFP transfusion caseload in order to more fully study reactions and efficacy in cats.

In a previous study of FFP usage in cats, hypoalbuminemia was the stated reason for transfusion in >50% of cases.⁶ In contrast, the primary documented reason for FFP transfusion in 94% of cats in our study was coagulopathy. All but one patient with coagulopathy were presumed to have acquired coagulopathies secondary to systemic disease processes or anticoagulant rodenticide toxicity; specifically, hepatopathy was over-represented. This is consistent with the findings of Dircks et al,²⁷ who reported that in cats with naturally occurring liver diseases (neoplasia, inflammation, hepatic lipidosis or other degenerative liver diseases), 98% had one or more abnormality of the coagulation parameters measured.

The population of this study included many critically ill cats that were administered 1–3 units of FFP. Many cases had poor prognostic indicators and comorbidities, including anemia, severe bleeding, surgical complications and suspected sepsis. We believe that the high mortality in our study cats was not related directly to FFP administration, but instead to the level of illness often seen at our facilities. Transfusion reaction rates in this study are somewhat higher than published data of pRBC transfusion reactions in cats and dogs (8–13%).^28,29 We believe this higher incidence is due to more intensive monitoring and expanded definitions rather than a true increased rate.

In human and veterinary medicine, the etiology of coagulopathy in critical illness is likely multifactorial, with inflammation suspected to play a key role.^4,30–34 A 2005 review of 25 medical studies of coagulopathic patients, defined by prolonged PT or an elevated international normalized ratio, that required invasive procedures concluded that there was insufficient evidence to indicate that these tests could predict bleeding.³⁵ PT and aPTT were not designed to predict bleeding and their applied clinical validity in wider settings such as the intensive care unit should be questioned.⁴ In critically ill human patients, it is still unclear whether administration of FFP reduces the risk of bleeding.^36–41 That said, plasma transfusions have continued to be recommended for human patients who are actively bleeding, or prior to surgery in coagulopathic patients.^12,42,43

In contrast to the human studies, one study in cats did show a higher risk of bleeding during ultrasound-guided biopsy with elevated aPTT values.⁴⁴ Some of the newer tests of hemostasis such as thromboelastogram (TEG), rotational thromboelastometry, thrombin generation assays, and platelet reactivity based on cytometry are more reflective of the cell-based model of coagulation and may be more appropriate tests for predicting bleeding.^4,45

This study confirms that FFP can improve coagulation times in cats. If no improvement in coagulation times is seen after one unit of FFP, transfusion of additional units should be considered. No strict guidelines exist for plasma dosing in animals or people, but 10–15 ml/kg FFP for treatment of PT or aPTT prolonged more than 1.5 times the upper limit of normal is the accepted practice in human medicine.⁴⁶ Twenty cats had pre- and post-FFP administration coagulation testing performed. Only two cases had no improvement or worsened PT or aPTT times post-FFP transfusion and neither case received multiple units.

Retrospective studies have limitations and can underestimate the occurrence of adverse events. A large prospective study with platelet counts and pre- and post-transfusion coagulation testing, including TEG and bleeding scores at set time points, would be useful for confirming the efficacy of plasma for treatment of coagulopathy in cats with different diseases. Use of predefined transfusion reaction definitions and grading would allow attribution of the adverse events either to the transfusion or other treatment or condition at the time by the attending clinician. Additionally, using the VCOG system in real time would be necessary to determine the correlation with prognosis and risk/benefit. Development of specific protocols for evaluation of respiratory signs, including thoracic radiographs, N-terminal pro-B type naturiuretic peptide testing and echocardiograms, would help better understand these reactions. Ideally, necropsies would be performed on cases that pass away with unknown etiologies.

Conclusions

This retrospective study provides safety and efficacy information for plasma transfusions in cats. Based on this study, FFP appears efficacious in individual cats at doses of 2.15–10.85 ml/kg for treatment of prolonged PT and/or PTT, and post-transfusion coagulation times should be monitored to be sure that the effective dose has been administered. FFP treatments in cats with suspected anticoagulant rodenticide poisoning show excellent outcomes when treated concurrently with vitamin K supplementation and other supportive care treatments. This study also demonstrates that cats should be monitored carefully for potential respiratory complications, fever and GI signs during and after plasma transfusion. Additional diagnostic tests should be considered to investigate whether the respiratory reactions are a TRALI or other etiology. Further studies are needed to clarify indications for FFP in coagulopathic cats with hepatopathy and/or sepsis.

Footnotes

Acknowledgements

The authors thank Michelle Mensing and Valentia Verena for their help with data collection.

Accepted: 26 August 2019

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

This work involved the use of non-experimental animal(s) only (owned and unowned), and followed established internationally recognized high standards (‘best practice’) of individual veterinary clinical patient care. Ethical approval from a committee was not necessarily required.

Informed consent

Informed consent (either verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work for the procedure(s) undertaken. No animals or humans are identifiable within this publication, and therefore additional informed consent for publication was not required.

ORCID iD

Elizabeth Mansi

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Retrospective evaluation of the indications,safety and effects of fresh frozen plasma transfusions in 36 cats (2014–2018)

Abstract

Objectives

Methods

Results

Conclusions and relevance

Keywords

Introduction

Materials and methods

Data collection

Blood donor screening, unit preparation and storage

Plasma administration

Transfusion reaction definitions, imputability and grading

Results

Coagulation testing and correction

Transfusion reactions and 7-day outcomes

Other

Discussion

Conclusions

Footnotes

Acknowledgements

Conflict of interest

Funding

Ethical approval

Informed consent

ORCID iD

References