An explicit association between DVT and trauma was first proved by Geerts in 1994.He performed serial impedance plethysmography and lower-extremity contrast venography in a cohort of 716 patients who were not receiving any type of DVT prophylaxis and discovered that 57.6% of trauma patients developed deep-vein thrombosis 9. In the Prophylaxis of Thromboembolism in Critical Care Trial (PROTECT), of 3764 critically ill patients who were receiving thromboprophylaxis medications, ultrasound screening revealed a proximal DVT rate of 5.1–5.8% 5. Incidence of DVT in TBI patients is three to fourfold higher than those patients without head trauma1. In a large multicenter trial, one in five patients with TBI developed VTE despite the use of chemoprophylaxis10.
Therefore, it seem prudent that DVT prophylaxis should be started as soon as possible. But the paradox of VTE prophylaxis is that any agent that decreases venous clot formation has a corresponding tendency to increase bleeding .Therefore, it is important to know whether this prophylaxis is really safe and effective or not. In one study, the rate of DVT in the cohort with no routine chemoprophylaxis was 5.6%, while the rate of DVT after routine chemoprophylaxis was 0%11. Another study from a Level I Trauma Center of patients with TBIs receiving early (0–72 hours) or late (> 72 hours) chemoprophylaxis found no evidence that early prophylaxis increases the rate of hematoma progression12. The Delayed Versus Early Enoxaparin Prophylaxis I (DEEP-I) randomized control trial found that intracerebral hematoma (ICH) progression rates among TBI patients receiving early prophylaxis were similar to those in patients who had been treated with placebo13. In another systemic review, out of twenty-one studies, eighteen studies confirmed that VTE prophylaxis in patients with stable head CT scan does not lead to TBI progression. Fourteen studies revealed that VTE prophylaxis administration 24 to 72 hours post-injury is safe in patients with stable injuries. Four studies suggested that administering prophylaxis within 24 hours of injury in patients with stable TBI does not lead to progressive intracranial hemorrhage14. Most recently, Störmann et al presented findings in which patients with severe TBI were categorized into four groups by timing of prophylaxis initiation: <24 hours, 24–48 hours, > 48 hours and no therapy. They showed that early (< 24 hours) administration was not associated with ICH progression15. Similar reductions in VTE rates were also observed and reported by Scudday, Saadeh, Rivas, Shulkosky 16,17,18,19.
Although, many meta-analysis revealed that early initiation of DVT prophylaxis is safe but some studies also warned about the danger of progression of intracranial bleeding. Prospective, multicenter, observational study sponsored by the Eastern Association for the Surgery of Trauma (EAST) Multicenter Trial Committee, observed that nearly 10% of TBI patients developed neurologic deterioration after the introduction of DVT prophylaxis 20. Another retrospective cohort study including 4951 patients who had neurosurgical interventions at trauma centers participating in the American College of Surgeons Trauma Quality Improvement Program between 2012 and 2016, noted that earlier initiation of prophylaxis was associated with increased risk of repeated neurosurgery and greater mortality. During the first 3 days, each additional day of prophylaxis delay was associated with a 28% decrease in odds of repeat neurosurgery. After 3 days, each additional day of prophylaxis delay was associated with an additional 15% decrease in odds of repeat neurosurgery. Each additional day of prophylaxis delay was also associated with decreased odds of death. These findings suggest that care should be taken in starting DVT prophylaxis during the first 3 days after the index procedure21.
With these alarming and conflicting reports, clinicians are in ambivalence to decide the real timing of DVT prophylaxis. Ideally, practice should be based on some authenticated guidelines but since nothing is clear therefore clinical practice is typically experience-based and subjective.
The question of when to start anticoagulation is not straightforward. The Eastern Association for the Surgery of Trauma (EAST) strongly recommends use of LMWHs in all trauma patients 22. American College of Surgeons Trauma Quality Improvement Project released guidelines in 2015, supporting consideration of VTE prophylaxis within the first 72 hours of hospitalization15. American College of Chest Physicians (ACCP) guidelines- published in 2012 & updated in 2016- also recommended the use of LMWH for major trauma patients as soon as it is considered safe23. National Institute for Health and Care Excellence (NICE) 2018 guidelines on preventing VTE in hospitalized patients endorsed interventions to reduce the incidence of VTE in the hospital and within 90 days after a hospital admission. American Society of Hematology Guidelines 2018 also advocate pharmacological prophylaxis for all ill patients6. Brain Trauma Foundation (BTF), simply states that anticoagulation should be used, but has not declared any timing of prophylaxis. BTF concluded that there is insufficient evidence to support recommended timing of VTE prophylaxis initiation following TBI24. Neurocritical Care Society recommends initiating LMWH or unfractionated Heparin for VTE prophylaxis within 24–48 h of presentation in patients with TBI. More recently, a systematic review from 2020 concluded that early chemoprophylaxis 24–72 hours is related to reduced VTE incidence without increasing the risk of intracranial hemorrhage15. But, in spite of all these guidelines, haziness still persists and precise timing for chemoprophylaxis remains uncertain.
Many options for anticoagulation are available but which medicine to choose is another puzzle. There are many controversies regarding drugs and the doses in DVT prophylaxis. Eastern Association for the Surgery of Trauma guidelines recommend use of low-molecular-weight heparin (LMWH) / enoxaparin as the preferred agent in patients with traumatic intracranial bleeding. Level one evidence also supports the use of LMWH in reducing the incidence of mortality and VTE events among trauma patients 25,26. In randomizing 265 patients to receive either enoxaparin or unfractionated heparin, Geerts et al. demonstrated a significant reduction in DVT rates from 44–31%, as well as in proximal DVTs from 15–6%, with the use of enoxaparin. This study also proved that 30 mg of subcutaneous enoxaparin twice daily performed better than 5,000 U of subcutaneous heparin twice daily at reducing DVT in moderate to severely injured trauma27. Also, enoxaparin was shown to have a neuroprotective effect in animal models as well as in humans following traumatic brain injury .Animal studies showed that enoxaparin reduced brain edema and secondary brain injury due to its anti-inflammatory effects. Enoxaparin also prevents thrombosis in cerebral microcirculation and reduces related damage 28. LMWH was shown to be superior to heparin in a double-blinded, randomized clinical trial among 344 trauma patients without frank intracranial bleeding27. The initial enoxaparin dose for trauma patients may also be based on weight like 0.5 mg/kg twice daily, or 30 mg for 50 to 60 kg patients, 40 mg for 61 to 99 kg patients, and 50 mg for patients greater than 100 kg 29,30. The advantages of using LMWH compared to other modalities are its ease of administration, increased efficacy, improved specificity, and no monitoring requirement 31. Therefore, enoxaparin 30 mg subcutaneously once or twice a day should be the preferred VTE prophylaxis agent for use in hospitalized trauma patients .
A judicious and appropriate use of DVT prophylaxis is another important issue. It has been noticed that if on one hand, DVT prophylaxis is being ignored than on the other hand it is either underutilized or overutilized. A 2008 multinational study of 358 hospitals in 32 countries showed that patients who were considered low risk for VTE tended to be “overprophylaxed,” with about one-third of both low-risk patients receiving prophylaxis that was not indicated. A retrospective observational study of Canadian hospitals showed that fewer than one-quarter of acutely ill patients were prescribed any form of VTE prophylaxis. US hospitals with only 12.7% of medical patients and 16.4% of surgical patients prescribed appropriate prophylaxis according to accepted guidelines. A study of hospital discharge information for > 70 000 cancer patients showed that only 53.6% were prescribed prophylaxis. A consortium of hospitals in Michigan examined 44 775 patients and also found that 77.9% of low-risk medical patients were prescribed excess prophylaxis, suggesting the indiscriminate use of prophylaxis 6. Therefore, it is important to ensure that high risk patients should not be missed for DVT prophylaxis but at the same time low risk patients should not be overexposed to DVT prophylaxis.
Our study showed that 65% of patients were suffering from mild to moderate head injuries based on GCS, ISS and DVT scores. Most of the patients were males with an average age of 35-years. Predominant cause of head trauma remained RTA. An average GCS of our patients was 11. Also, averages ISS was 14 whereas ISS > 15 is considered as severe trauma. Although there are several DVT scoring systems, the Wells DVT score, the Wells PE score, and the Geneva PE score are the most widely used and best validated scores6. We calculated DVT score on the basis of Caprini model as per hospital policy. The 2013 Caprini risk assessment model has been validated in over 250 000 patients in more than 100 clinical trials worldwide. It provides a consistent, thorough, and efficacious method for risk stratification and selection of prophylaxis for the prevention of DVT. As the numerical score increases, the clinical DVT rate rises exponentially. But cutoff score between risk groups varies depending on the surgical population7. Our average DVT score based on Caprini criteria was 7.7 which is tantamount to mild to moderate head injuries.
Our fifty-three percent patients were polytraumatized. Overall, 40% needed surgical intervention like neurosurgical/ orthopedic/ maxillofacial procedures. Neurosurgical procedures are classified as very high hemorrhagic surgical procedures, making the management of anticoagulation in neurosurgery one of the toughest challenges 32. Therefore, it was natural to have a delay in prescription of chemoprophylaxis. We also noticed significant hesitancy among other surgical specialties in initiation of prophylaxis. No one shouldered this responsibility and ultimately neurosurgeons had to resolve when to start or resume prophylaxis. In spite of all these odds,
50% patients received early chemoprophylaxis that is within 72 hours; 25% received late prophylaxis and 25% patients received mechanical prophylaxis. Although literature supports the effectiveness of mechanical prophylaxis but compression devices are not effective for upper limb, pelvis and catheter-related venous thromboses, which all continue to be potential sources of pulmonary embolism in high-risk critically ill TBI patients5.
We noticed that surgeons usually preferred heparin but due to shortage of supply finally most of the patients had to be shifted on enoxaparin. Patient remained on chemoprophylaxis until discharge or until patients could ambulate independently. There was no interruption of DVT prophylaxis once it was started. Our average delay was 2.9 days which is unarguably acceptable. Similar results have been recently reported in a retrospective study from Kingdom of Saudi Arabia33.
We did not observe any progression of intracranial hemorrhage in any patient after initiation of chemoprophylaxis. We also did not notice any cases of pulmonary embolism. Nevertheless, 2.5% developed some sort of thrombosis in the body. Our findings clearly show that our current clinical practice is commensurate with international standards and guidelines. This study also revealed that fear of ICH progression is unjustified, irrational and illogical. Initiation of chemoprophylaxis within 72 hours in head injuries even in polytraumatized patients is sagaciously advisable.
Our study has some limitations as well. Firstly, we were not able to record exact time interval between timing of injury/accident and arrival of patients at our institution in many patients but it was not more than 24 hours. This could result in a bias in calculating the exact time interval from the time of injury to the time of initiation of prophylaxis. Secondly, low GCS of patients at the time of admission was not accurate because of their sedation for intubation and ventilation from the referring hospitals. Their GCS improved when sedation was gradually tapered off. Hence, this subset of severe traumatic brain injury with GCS < 8 is not a representative sample. Thus, our judgement regarding timing of DVT prophylaxis in severely head injured patients may not be valid. Thirdly, our prescribed doses of heparin and enoxaparin were neither appropriate nor guided by anti-Xa levels and weight. We prescribed these medicines for all patients as standard and fixed doses whereas ideally these should be calculated on a weights basis. Because, obesity in Saudi Arabia is a growing health concern, and our average BMI has also tilted towards the higher side. Hence weight-based prescription of DVT chemoprophylaxis could be a sensible option to be practiced. Finally, we did not undertake any scrutiny for occult or asymptomatic DVT, either during hospitalization or after discharge proactively. Literature review indicates that DVT proportions are increased whenever routine surveillance techniques are used34. But routine screening of patients for DVT is logistically difficult and is not cost-effective. Also, currently, there are no explicit standards for ordering imaging tests to confirm or exclude a VTE outside of clinical judgment 6. Strength of our study is that we mentioned BMI as an important covariable between DVT prophylaxis and TBI.
Our study lucidly shows that DVT prophylaxis is safe within 24 hours in head injured patients with or without polytrauma. There is neither any progression nor any development of new hemorrhages. Even after major neurosurgical procedures, initiation within 72 hours of DVT prophylaxis was found safe. Although, heparin is cost-effective but enoxaparin is more efficacious and neuro-protective35.
Based on the available literature, we can cautiously conclude that early DVT prophylaxis reduces the risk of VTE without affecting progression of intracerebral hemorrhage36. Thromboprophylaxis should never be deferred on the basis of an irrational fear of its side-effects37. It provides an opportunity both to improve patient outcomes and also to reduce hospital costs .The International Society on Thrombosis and Haemostasis has recently put forward a call for risk assessment in all hospitalized patients and pledged to reduce hospital-acquired VTE by 20% by the year 2030 6.