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Three Part Question

In [patients with solid organ injury following blunt abdominal trauma] is [chemical thromboprophylaxis] a [safe early intervention in non-operative clinical management]

Clinical Scenario

A 45 year old man (Mr X) sustained significant trauma in a road traffic accident (RTA). From clinical examination and a trauma series CT scan Mr X is diagnosed with grade 3 liver and splenic injuries. Mr X is haemodynamically stable and has no evidence of ongoing bleeding, initial plan is to manage the patient non-operatively. Mr X is in significant discomfort and is not mobilising from bed, you wonder about the safety of prescribing low molecular weight heparin (LMWH) venous thromboembolism (VTE) prophylaxis.

Search Strategy

Using search terms:
(thrombus* OR thrombotic* OR thrombolic* OR thromboemboli* OR thrombos* OR thromboph* OR deep* OR vein* or ven* OR thromb* or embol* OR pulmonary OR lung* OR thromb* OR embol* OR DVT or PE or VTE)
AND (solid organ injury OR organ injury OR blunt abdominal trauma OR abdominal injury OR Abdominal trauma OR blunt trauma OR abdominal organ injury OR splenic injury OR liver injury OR kidney injury OR splenic trauma OR liver trauma OR kidney trauma) AND (thromboprophylaxis OR prophylactic* OR prophylaxis)

Searching databases Medline (1946 - September 2017), Embase (1974 - September 2017) and Cinahl (1981 - September 2017) via NHS NICE Healthcare Databases Advanced Search (HDAS) interface.
And Cochrane Central Register of Controlled Trials (September 2017) & Cochrane Database of Systematic Reviews (September 2017)


Search Outcome

910 papers were identified. After reviewing title and abstract of 910 papers, 901 papers were excluded to only include original studies assessing safety of pharmacological thrombo-prophylaxis in patients with blunt solid organ injuries receiving NOM.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Norwood S, et al 2001 USA	22 Patients suffering blunt trauma who received LMWH in <24 hours of which 8% had liver injuries n= 10, and 10% had splenic injuries n= 12	Prospective cohort study	Failure of NOM	No patient with liver injury failed NOM, however, two of the 12 patients with splenic injuries failed NOM, both had a high grade injury	Small sample of patients with abdominal solid organ injury (SOI)
Alejandro K, et al 2003 Puerto Rico	114 Patients over 18 years old sustaining blunt trauma splenic injuries, initially being managed nonopratively, receiving LMWH thrombo-prophylaxis; Early (<48 hours) n= 50 or Late (>48 hours) n= 64	Retrospective cohort study, level 3	Failure of nonoperative management (NOM)	No statistical difference in failure of NOM between early or late thrombo-prophylaxis groups p= 0.593	Relatively small sample size. The late group includes patients who did not receive LMWH . It was not statistically significant but a higher proportion of patients in late LMWH group had moderate-severe splenic trauma. This study only included patients with splenic injury.
				Failure rate of NOM is low 4% in early 6% in the late group
			Requirement of blood transfusions (BT)	Requirement of blood transfusions were similar p= 0.507
Eberle BM et al 2011 USA	312 Patients over 15 years old with blunt liver, kidney or splenic trauma being managed non-operativley receiving LMWH; Early <3 days n= 41 (13.2%), Late >3 days n= 70 (22.4%), No LMWH n= 201 (64.4%)	Retrospective cohort study, level 3.	Failure of NOM	The overall failure rate of NOM was 7.8% for splenic trauma	Significant differences exist between comparison groups, for example the average injury severity score was higher in patients in the late LMWH group. Pelvic and lower extremity fracture were significantly more common in the early and late LMWH groups compared to the group not receiving LMWH p=0.001. The study did not use routine screening to aid diagnosis of thromboembolic disease.
				No difference in rates of NOM failure between the early, late or no LMWH groups.
				11 patients had high grade splenic injuries and received early LMWH which did not result in a significant difference in failure of NOM compared to late or no LMWH groups p=0.766
				In liver and kidney trauma, no significant differences in failure of NOM
			Packed red cell transfusion requirements	Greater requirement of PRBC in the late LMWH compared to early LMWH group
			Incidence of DVT or PE, diagnosed clinically (not through routine screening)	Four cases of thromboembolic disease, overall incidence of 1.3%, all occurred before the administration of LMWH. Diagnosed clinically.
Joseph B et al 2015 USA	145 Patients with blunt solid organ injuries (liver, kidney, spleen) who underwent NOM and received VTE prophylaxis during admission; Early <48 hours n= 58, Intermediate 48 to 78 hours n= 29 and Late >72 hours n= 29	Retrospective cohort study level 3	Failure of NOM	No patient failed NOM	Relatively small sample size
			Requirement of angioembolisation	One patient in each group required angio-embolisation, all of these patients had high grade splenic injuries
			Blood product requirement	No significant difference of requirement for blood products
			Incidence of VTE	Two patients with high grade injuries developed DVT, one in the intermediate and one in the late group
Rostas J, et al 2015 USA	328 patients receiving NOM with blunt liver and splenic trauma receiving LMWH prophylaxis Early <48 hours n= 103 (31%) intermediate 48 - 72 hours n= 54 (17%) late >72 hours n= 171 (52%)	Retrospective cohort study level 3	Failure of NOM following administration of LMWH	No patients failed NOM after administration of LMWH	Comparing groups, the high grade liver and splenic injuries were were more often selected to not receive early LMWH.
			Blood products required	No difference in amount of blood products required
			Incidence of VTE (diagnosed clinically, not through routine screening)	One patient (0.6%) in the early group developed VTE, no cases of VTE in intermediate group but 2.8% 6 in the late group developed
Murphy P, et al 2015 Canada	162 Patients over 18 years old sustaining blunt trauma splenic injuries, being managed nonopratively, receiving LMWH thrombo-prophylaxis; Early (<48 hours) n= 78 or Late (>48 hours) n= 84	Retrospective cohort study, level 3	Failure of non-operative management (NOM); operative intervention or embolisation.	No statistically significant difference in NOM failure.	Significantly more high grade splenic injuries were in the delayed (late) LMWH group. The late LMWH group included patients who did not receive LMWH. This study only included patients with splenic injury. No screening to diagnose VTE.
			Blood transfusion requirement	No difference in requirement of blood transfusions
			Incidence of VTE (diagnosed clinically, not through routine screening)	Two cases of PE and one DVT in the early prophylaxis group
kwok A, et al 2016 USA	474 Patients over 13 years old sustaining blunt trauma splenic injuries; Immediate <24 hours n= 23, Early (24-48 hours) n= 91 or intermediate (48-72 hours) n= 65, late >72 hours n= 77 and patients who did not receive LMWH n= 241	Retrospective cohort study, level 3	Failure of non-operative management; operative intervention or embolisation.	LMWH administration did not increase failure of non-operative management p= 0.39	Significant differences exist between the comparison groups; despite the group not receiving VTE prophylaxis having a greater number of grade IV splenic injury, this group had a lower average injury severity score. Patients with high grade splenic injuries that received LMWH were more often prescribed delayed VTE prophylaxis. This study only included patients with splenic injury.
				No significant difference in failure of NOM between groups of patients who receive LMWH immediately, early, intermediate or late p= 0.95
			Blood products received	No significant difference in requirement of blood products
Khatsilouskaya T, et al 2017 Switzerland	179 Adult trauma patients with solid organ injury (SOI) (liver, spleen, kidney) undergoing NOM. LMWH or unfractionated heparin given; Early <72 hours n= 80 , Late >72 hours n= 62, or None given n= 37	Retrospective cohort study	Failure of NOM	Failure rate of NOM was 3.9%	The injury severity score (ISS) was significantly higher in the late heparin group. Significantly more patients with pelvic and lower limb fracture received anticoagulation compared to the no heparin group p=0.012. Significantly more high grade SOI in the no heparin group.
				Failed NOM occurred in patients with splenic injuries, more common in the no heparin group compared to late or early heparin, (10.8, 4.8 and 1.3% respectively) p= 0.043
			Incidence of VTE (diagnosed clinically, not through routine screening)	No statistically significant difference of VTE incidence, however, more often VTE was diagnosed in patients from the late and no heparin group.

Comment(s)

Non-operative management (NOM) of blunt trauma solid organ injury (SOI) in haemodynamically stable patients has become standard practice of care.(9,10) 
Venous thromboembolism (VTE) is a life threatening complication of major trauma.(11) Prothrombotic changes in physiology are hypothesised to occur within 48 hours following trauma.(12) Chemical VTE prophylaxis is superior to mechanical VTE prophylaxis.(13) Mechanical prophylaxis may be precluded in blunt trauma if there is associated lower limb injury. The American College of Chest Physicians and Eastern Association for the Surgery of Trauma clinical guidelines suggest early administration of chemical VTE prophylaxis,(14,15) but do not specify its timing, and there is a lack of evidence to inform of its safety in early NOM of blunt trauma SOI. 
Most current evidence assessing the safety of early chemical thrombo-prophylaxis (low molecular weight heparin or unfractionated heparin) are retrospective cohort studies. Retrospective cohort studies are vulnerable to selection bias as patients enter respective treatment arms depending at the discretion of the treating physician. In many of the studies, significant differences existed in the grade of traumatic injury between the respective treatment arms. Discrepancies in these groups likely reflect the treating physicians reluctance to initiate low molecular weight heparin (LMWH) in patients identified to have a high grade SOI. Many of the studies available have relatively small sample sizes to detect differences in failure of NOM. Eberle et al reported failure of NOM for patients not receiving thrombo-prophylaxis of 7%,(4) which means to detect a difference of 10% in failure rates with 80% power a study requires a sample size of 165 patients in each respective comparison group. Only two studies investigated administration of LMWH within 24 hours, Norwood et al in a prospective study which did not include a comparison group and Kwok et al who did not find that administration of LMWH within 24 hours increased failure rate of NOM or requirement of blood products. There are differences between the studies in patient population, chemical prophylaxis regimens, and the classification of early and late administration. Most studies used LMWH and defined early administration of LMWH as occurring within 48 hours. These studies show that administering LMWH within 48 hours does not increase failure rate of NOM or the increase the requirement for blood products. These studies suggest that administration of LMWH within 48 hours is safe in patients who sustain SOI from blunt trauma being receiving NOM. References 1) Norwood SH, McAuley CE, Berne JD, et al. A potentially expanded role for enoxaparin in preventing venous thromboembolism in high risk blunt trauma patients. J Am Coll Surg (2001); 192: 161-167 2) Alejandro KV, Acosta JA, Rodriguez PA. Bleeding manifestations after early use of low-molecular-weight heparins in blunt splenic injuries. Am Surg. (2003); 69: 1006 –1009 3) Eberle BM, Schnu ̈riger B, Inaba K, et al. Thromboembolic prophylaxis with low-molecular-weight heparin in patients with blunt solid abdominal organ injuries undergoing non-operative management: current practice and outcomes. J Trauma Acute Care Surg (2011); 70: 141–147 4) Joseph B, Pandit V, Harrison C et al. Early thromboembolic prophylaxis in patients with blunt solid abdominal organ injuries undergoing nonoperative management: is it safe? Am J Surg (2015); 209: 194–198 
5) Murphy PB, Sothilingam N, Stewart TC, et al. Very early initiation of chemical & venous thromboembolism prophylaxis after blunt solid organ injury is safe. Can J Surg (2016); 59: 118–122 6) Kwok A, Davis J, Dirks R, Wolfe M, Kaups K. Time is now: venous thromboembolism prophylaxis in blunt splenic injury. Am J Surg (2016); 212: 1231-1236
 7) Rostas JW, Manley J, Gonzalez RP et al. The safety of low molecular-weight heparin after blunt liver and spleen injuries. Am J Surg (2015); 210: 31–34 8) Khatsilouskaya T, Haltmeier T, Cathomas M, Erberle B, Candinas D, Schnuriger B. Thromboembolic Prophylaxis with Heparin in Patients with Blunt Solid Organ Injuries Undergoing Non-operative Treatment. World J Surg (2017); 41: 1193-1200 9) Stassen NA, Bhullar I, Cheng JD et al. Nonoperative management of blunt hepatic injury: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg (2012); 73: 288–293 
 10) Zarazur BL, Kozar R, Myers JG, et al. The splenic injury outcomes trial: an American Association for the Surgery of Trauma multi- institutional study. J Trauma Acute Care Surg (2015); 79: 335–42 11) Geerts WH, Code KI, Jay RM et al. A prospective study of venous thromboembolism after major trauma. N Engl J Med (1994); 331:1601–1606 

 12) Chapman BC, Moore EE, Barnett C, et al. Hypercoagulability following blunt solid abdominal organ injury: when to initiate anticoagulation. Am J Surg. (2013); 206: 917–22. discussion 922–3 
 13) Barrera LM, Perel P, Ker K, Cirocchi R, Farinella E, Morales Uribe CH. Thromboprophylaxis for trauma patients. Cochrane Database Syst Rev. (2013); (3): CD008303 
 14) Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest (2012); 141: e419S–94S. 15) Rogers FB, Cipolle MD, Velmahos G, et al. Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group. J Trauma (2002); 53: 142-164.

Clinical Bottom Line

There is inadequate evidence assessing safety of LMWH within 24 hours of trauma.
The current available evidence of retrospective studies do suggest that administration of LMWH within 48 hours is safe in early NOM of patients who have sustained SOI from blunt trauma. However, a large multi centre randomised prospective study is warranted to investigate further before confidently concluding the safety of early chemical thomboprophylaxis in early NOM of SOI.

References

1. Norwood SH, McAuley CE, Berne JD, Vallina VL, Kerns DB, Grahm TW, McLarty JW A potentially expanded role for enoxaparin in preventing venous thromboembolism in high risk blunt trauma patients. Journal of the American College of Surgeons (J Am Coll Surg) (2001); 192: 161-167
2. Alejandro KV, Acosta JA, Rodriguez PA Bleeding manifestations after early use of low-molecular-weight heparins in blunt splenic injuries. The American Surgeon (Am Surg) (2003); 69: 1006 –1009
3. Eberle BM, Schnu ̈riger B, Inaba K, et al. Thromboembolic prophylaxis with low-molecular-weight heparin in patients with blunt solid abdominal organ injuries undergoing non-operative management: current practice and outcomes. The Journal of Trauma: Injury, Infection, and Critical Care (J Trauma) (2011); 70: 141–147
4. Joseph B, Pandit V, Harrison C, Lubin D, Kulvatunyou N, Zangbar B, et al Early thromboembolic prophylaxis in patients with blunt solid abdominal organ injuries undergoing nonoperative management: is it safe? American Journal of Surgery (Am J Surg) (2015); 209: 194–198
5. Rostas JW, Manley J, Gonzalez RP, Brevard SB, Ahmed N, Frotan MA, et al. The safety of low molecular-weight heparin after blunt liver and spleen injuries. American Journal of Surgery (Am J Surg) (2015); 210: 31–34
6. Murphy PB, Sothilingam N, Stewart TC, Batey B, Moffat B, Gray D, et al. Very early initiation of chemical & venous thromboembolism prophylaxis after blunt solid organ injury is safe. Canadian Journal of Surgery (Can J Surg) (2016); 59: 118–122

7. Kwok A, Davis J, Dirks R, Wolfe M, Kaups K Time is now: venous thromboembolism prophylaxis in blunt splenic injury. American Journal of Surgery (Am J Surg) (2016); 212: 1231-1236

8. Khatsilouskaya T, Haltmeier T, Cathomas M, Erberle B, Candinas D, Schnuriger B. Thromboembolic Prophylaxis with Heparin in Patients with Blunt Solid Organ Injuries Undergoing Non-operative Treatment. World Journal of Surgery (World J Surg) (2017); 41: 1193-1200