Case report: Heparin coagulant super-sensitivity during leech therapy

Abstract

Background

Leech therapy is used in diverse ways in the medical field, such as for flap salvation and for treatment of osteoarthritis. While bleeding is a recognized adverse effect, severe coagulopathy is rare and underreported, especially when compounded by concurrent anticoagulant use.

Case presentation

We present a case of a 76-year-old female undergoing leech therapy in combination with systemic heparin for free flap salvage following partial glossectomy and neck dissection. Shortly after initiating both therapies, the patient developed marked coagulopathy, evidenced by prolonged activated partial thromboplastin time (aPTT), elevated thrombin time, and persistent bleeding from the surgical site. Laboratory results suggested synergistic anticoagulant effects of heparin and hirudin, the potent direct thrombin inhibitor secreted by medicinal leeches. Despite discontinuation of systemic heparin, bleeding persisted until leech therapy was halted. The patient received 8 units of packed red blood cells (pRBCs) during the treatment course. Coagulation markers normalized after cessation of leech therapy, with no further bleeding events.

Conclusions

This case highlights a potentially underrecognized risk of coagulopathy in patients undergoing combined leech and systemic anticoagulation therapy. The mechanistically distinct pathways of heparin and hirudin may act synergistically to impair both free and clot-bound thrombin activity. Given the absence of formal guidelines for coagulopathy monitoring in such cases, we propose daily assessment of coagulation markers including aPTT, PT/INR, and a one-time measurement of thrombin time and anti-Xa levels after treatment initiation. This report underscores the need for standardized protocols and further research to guide safe implementation of leech therapy, particularly in patients receiving systemic anticoagulation.

Background

Leech therapy, also known as hirudotherapy, is a medical treatment that involves the use of live medicinal leeches (Hirudo medicinalis) to extract blood and introduce therapeutic substances into the body [1]. The leeches secrete many bioactive compounds, including anticoagulants and anesthetics, which can promote healing, improve circulation, and reduce inflammation [1]. This practice, which dates back to ancient civilizations, has been revived in modern medicine for its potential therapeutic benefits.

From a hematologic perspective, the therapeutic value of leeches comes from the anticoagulation and antiplatelet effects. Blood clotting is fatal for leeches during feeding [1]. Leeches secrete inhibitory enzymes such as apyrase, saratin, calin and leech antiplatelet protein to prevent primary hemostasis through mechanisms such as inhibition of von-Willebrand Factor (vWF)-collagen reaction and facilitation of adenosine diphosphate (ADP) to adenosine monophosphate (AMP) conversion [2–5]. More importantly, leeches secrete potent anticoagulants such as hirudin and factor Xa inhibitors which prevent secondary hemostasis through inhibition of thrombin and factor Xa [6, 7]. Figure 1 is a simplified diagram of hirudin’s mechanism of action in the coagulation cascade in comparison with heparin.

Fig. 1.

Hirudin’s mechanism of action in the coagulation cascade. Hirudin binds to both the active site of Thrombin (factor IIa) and to Exosite 1, the substrate binding site, to inhibit thrombin function. In comparison, heparin binds to antithrombin and potentiates antithrombin binding to thrombin’s active site, inhibiting thrombin function

Leech therapy has been used medically in diverse ways. In plastic and reconstructive surgery, leeches are used to relieve venous congestion in compromised flaps by preventing flap thrombosis and necrosis [8]. Leech therapy has also been studied in the treatment of osteoarthritis (OA). It has been shown in randomized, controlled trials that leeches can improve functionality and joint stiffness in OA patients for at least 3 months [9]. Until now, leech therapy is approved by the U.S. Food and Drug Administration (FDA) only as a medical device as “an adjunct to the graft tissue healing when problems of venous congestion may delay healing, or to overcome the problems of venous congestion by creating prolonged localized bleeding [10]”. In addition, medicinal leeches are currently listed as unclassified medical devices under FDA regulations – meaning that leeches, as a device, do not belong to the three currently existing medical device classes. An unclassified medical device is a pre-amendments device for which a classification regulation has not been promulgated [11]. Despite the overall great safety profile, the most common complications of leech therapy include infection, allergy, and bleeding [12]. A few cases of clinically severe bleeding due to leech therapy or leech bites have been reported [13–15] where leech bites resulted in hemorrhagic shock, coagulopathy or clinically significant gastrointestinal bleeding. Given that bleeding is a very common complication of leech therapy with up to 50% of patients receiving leech therapy for flap salvation requiring transfusion during treatment course, most guidelines for bleeding prevention during leech therapy focuses on monitoring hemoglobin (Hgb) and hematocrit (Hct) [8, 12, 16]. Routine monitoring of coagulation profile including measurement of international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (aPTT) has not been widely recommended. However, given the known anticoagulation effect of leech secretions, it is likely that concurrent administration of anticoagulation medications such as heparin could potentiate bleeding tendency in patients receiving leech therapy. In this report, we present a case of prolonged bleeding and elevated coagulation markers in a patient treated with leech therapy for flap venous congestion.

Case description

The patient is a 76-year-old female with Sjogren syndrome and newly diagnosed T2N2a squamous cell carcinoma of the right lateral oral tongue. The patient underwent right partial glossectomy, right modified radical neck dissection and left radial forearm free flap reconstruction for primary treatment of her cancer. She was admitted postoperatively to surgical ICU for routine hourly flap checks. On post operative day 5 (POD 5), the intraoral free flap showed a dusky appearance, raising concern for venous congestion and leading to flap pedicle revision with saphenous vein grafts. Continuous heparin infusion was started for the patient on the same day of graft revision, and leeches were applied the night after completion of flap revision. Before initiation of heparin infusion, the most recent weight in the patient’s medical record was 54.9 kg (121.0 lb) and her body mass index (BMI) was 23.15. As shown in Fig. 2D, the first significantly elevated value of 151 s was 10 h before the initiation of continuous heparin infusion but 23 min after the first intravenous (IV) heparin bolus infusion that was given intra-operatively during flap revision. A total of 11870.66 units of IV heparin bolus was given during flap revision, which was followed by continuous heparin infusion about 7 h after the last bolus was given during surgery. Her coagulation markers were markedly elevated on day 1 of continuous heparin infusion with a peak aPTT of 173.9 s. On POD 6 (one day after revision), the patient started to have slow bleeding from her oral surgical site. Heparin infusion rate was adjusted to a goal aPTT of 73.6 s on the same day but infusion was discontinued later that day due to continued bleeding. The patient also received 2 units of packed red blood cell (pRBC) transfusions because her hemoglobin decreased to 8.7 g/dL in the setting of post-operative bleeding. The patient was later transitioned to prophylactic subcutaneous heparin injections when bleeding resolved but continued to have prolonged mild bleeding when receiving leech therapy, so hematology was consulted. Over the next few days, the patient had intermittent elevation in her coagulation markers such as aPTT, PT and INR while only receiving subcutaneous prophylactic heparin and leech therapy. Further coagulation studies were obtained which showed an elevated thrombin time at 37.6 s (normal 18.2–26 s), anti-factor Xa assay of 0.13 U/ml and normal reptilase time of 13.8 s (normal < 23 s). A detailed graph of coagulation marker trends during the leech therapy course is shown in Fig. 2. Given the coagulation test results and continued bleeding, leech therapy was discontinued on POD 10 given high suspicion for hirudin effect. Patient’s coagulation markers subsequently normalized with no significant bleeding events afterwards. During the time that the patient received leech therapy (POD 5 – POD 10), she received 6 units of pRBC in total. The patient received another 3 units of pRBC after the termination of leech therapy, including 2 given on POD 11 and 1 given between POD 12 and discharge. The patient’s platelets remained above the lower limit of normal throughout hospitalization (range 150,000/mcL to 604,000/mcL). There were no major procedures performed during the remainder of her hospitalization. The patient remained stable with good progression in swallowing function and was discharged on POD 33 to home.

Fig. 2.

Relevant lab markers, heparin dosing and leech exposure time during hospitalization. For panel A-D, given there were several days where more than 1 measurements were obtained per day, measurements that occurred on the same day are listed from left to right chronologically. Baseline values for each parameter are denoted by dashed lines obtained 18 days before the date of surgery and are listed here: Hgb 13.1 g/dL (normal range: 12–16 g/dL), PLT 276,000/mcL (normal range: 150–350,000/mcL), PT 11.4 s (normal range: 9–13.7 s), aPTT 30.4 s (normal range: 22.8–40.8 s). Normal ranges are presented as shaded gray rectangles on each panel through A-D. (A) Hgb trend during hospitalization. Each black arrow above the Hgb curve represents 1 unit of pRBC transfusion. The time of flap revision, heparin infusion initiation and leech therapy initiation are marked using arrows under the Hgb curve. (B) PLT trend during hospitalization. (C) PT trend during hospitalization. (D) aPTT during hospitalization. Special coagulation studies including Anti-Xa assay, Thrombin Time (normal range: 18.2–26.0 s) and Reptilase Time (normal < 23.0 s) are all marked on graph with arrow. (E) Total Heparin dose (in units) each day during hospitalization. After POD 7, heparin infusion was switched to subcutaneous heparin injections. Values after POD 7 are purely subcutaneous doses. (F) Total leech exposure each day in minutes during hospitalization

Discussion and conclusions

Leech therapy has various applications, such as treatment of flap venous congestions, osteoarthritis pain control as well as helping with wound healing [1]. As mentioned before, bleeding is a common adverse effect of leech therapy with some severe cases requiring blood transfusions [8]. To prevent complications from leech therapy related bleeding, it is generally recommended to monitor Hgb and transfuse to a Hgb goal of above 8 g/dL [8]. The average transfusion requirement during leech therapy is 3–6 units of pRBC during flap salvation [8].

Several factors can contribute to excessive bleeding in patients receiving leech therapy. The synergistic effect of the co-administration of hirudin and heparin arises from their complementary but mechanistically distinct modes of thrombin inhibition. Heparin acts indirectly by enhancing the activity of antithrombin III, which inactivates circulating thrombin and factor Xa. However, its efficacy is limited against thrombin already bound to fibrin, as the antithrombin-heparin complexes cannot easily access these sites. In contrast, hirudin, secreted by medicinal leeches, binds directly and irreversibly to thrombin, targeting both its catalytic active site and Exosite 1, a key anion-binding region involved in substrate recognition. This dual binding allows hirudin to inhibit both free thrombin and clot-bound thrombin [17]. The combination of systemic heparin and localized hirudin exposure, as seen in this case report, may have resulted in synergistic anticoagulation. In contrast, patients undergoing leech therapy for osteoarthritis (OA) typically do not receive systemic anticoagulation, which may explain the absence of significant bleeding reported in that context [9]. In a prospective protocol review of leech therapy use in treating flap venous obstruction by [18]; systemic anticoagulation was administered to all 8 patients in the study, including 4 that received IV heparin. No hematoma was seen in relation to anticoagulation measures. However, the authors in this review recognized that opinions vary among surgeons on the concomitant use of systemic anticoagulation with leech therapy and that the combined effect of hirudin and heparin may have increased bleeding risk, as 6 out of 8 patients required transfusion during leech therapy [18]. The continued elevation in aPTT in this patient may also be explained by the complicated pharmacokinetics of hirudin. Heparin’s half-life varies from 30 to 120 min depending on the administered dosage [19]. While this is comparable to the half-life of recombinant hirudin, which varies from 60 to 120 min [19] , leech-secreted hirudin can have complicated behavior in the human body, with clinical evidence that hirudin’s effect may be present up to 2 to 4 h after leech detachment [20], which may contribute to the prolonged aPTT elevation in this patient. The combined anticoagulation effect seen in our case, supported by literature review, underscores the importance of closely monitoring coagulation lab parameters and carefully fine-tuning dosage or duration limits when combining these therapies.

Another important factor to consider is the protocol of leech therapy. Bleeding events that require transfusion are uncommon in patients receiving leech therapy for OA [9]. Slight Hgb drop is observed in OA patients after leech therapy with no clinically relevant bleeding event [9]. The stark difference in rate of clinically significant bleeding can partly be attributed to the total duration of leech application. When used for treatment of flap venous congestion and flap salvation, 1–5 leeches can be applied up to every 2 h with each application lasting 30–90 min for a total duration of 4.6 days on average [8, 16]. In a randomized trial that studied leech therapy use in OA patients, 4–6 leeches were applied for 70 min on average for only 1 session per patient [9]. This difference in total leech feeding time may explain the difference of clinically significant bleeding events when anticoagulative factors begin to accumulate in the patient’s system, as is observed in our patient’s case. It is well recognized that the total time of leech application and number of leeches applied during treatment vary considerably [8, 16], which can also contribute to the development of excessive bleeding. According to the review by [18]; leech therapy safety guidelines are well established, but published protocols are lacking. This review also concluded that consistent leech therapy protocol application ensured successful graft salvation. Therefore, consistency in leech therapy protocol detailing duration and quantity of leeches appears to be of importance in minimizing adverse effects.

Thrombo-inflammatory pathways intersect to regulate coagulation, thrombin generation, and the thrombo-hemorrhagic balance [21], largely driven by endothelial cell-derived tissue factor and suppression of anti-fibrinolytic responses. This patient had Sjogren’s syndrome which is characterized by immune-mediated inflammation, and is known to be associated with elevated thrombotic risk, thereby providing relative protection against bleeding risk in this patient [22]. In contrast, Sjogren’s syndrome is also associated with immune-mediated thrombocytopenia (AITP), although not present in this patient. Factors contained in leech salivary secretion have anti-inflammatory properties, which could have theoretically decreased the coagulability of our patient. Collagenase has been shown to both prevent initiation of platelet aggregation [23] and decrease infiltration of inflammatory cells [24]. Apyrase is well-known to inhibit platelet aggregation through ADP degradation [25] as well as exhibit anti-inflammatory activities [26]. Therefore, the anti-inflammatory properties of these factors contained in leech saliva may have dampened the known inflammation-induced coagulation response.

The patient’s sex and weight may have contributed to her sensitivity to heparin and hirudin. At the time of heparin administration, her weight was 54.9 kg (BMI 23.5 kg/m²). During the course of 2 days of heparin infusion, the patient received on average 275.2 units/kg of heparin. Inaccuracy in height and weight measurement during hospitalization should also be taken into account. Female patients have been known to have hypercoagulability as compared to their male counterparts, mainly characterized by shorter clotting time, increased clot propagation, increased clot strength and decreased clot lysis [27]. The difference in coagulation is generally attributed to higher female sex hormone level which increases thrombin generation [27], and in principle would have provided bleeding risk protection. To our knowledge, there is no sex-based predilection for exaggerated hemorrhage in patients exposed to leech therapy.

According to current literature, there is a lack of formal guidelines on leech and heparin co-administration. Furthermore, the role of coagulation marker monitoring has not been widely recognized, which may be beneficial for patients receiving leech therapy given that increased duration of exposure to leech secreted anticoagulant such as hirudin may increase bleeding risk, necessitating treatment with reversal agents. One recent review concluded that there is no consensus among microvascular surgeons regarding the use of systemic anticoagulation in flap salvation [28]. In another review, hematologic and clinical evaluation every 4 h was recommended for patients on leech therapy due to concern for major bleeding [18]. A few severe cases of leech bite induced coagulopathy have been reported which required treatment with tranexamic acid or fresh frozen plasma [13, 15].

In conclusion, our case report calls attention to the importance of understanding leech anticoagulant induced bleeding and further investigation into the role of coagulation marker monitoring. We propose daily monitoring of coagulation markers during treatment with both leeches and IV heparin as well as anti-Xa activity and thrombin time upon exposure to both leeches and IV heparin as a potentially useful strategy to minimize adverse bleeding effects. In general, the thrombin time is quite sensitive to direct thrombin inhibitors (i.e. hirudin, hirudin analogs), while the anti-Xa assay is an optimal parameter for heparin responsiveness, displaying little to no interference from direct thrombin inhibitors. Our case report highlights the need for more research and development of higher quality guidelines regarding prevention and monitoring of leech therapy related coagulopathy, especially in those receiving therapeutic anticoagulation at the same time.

Author contributions

ZR contributed majorly to the writing of this manuscript. AD and KL participated in the writing of the manuscript with significant contributions. LC and WB supervised and reviewed the manuscript writing process.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

Our institution does not require ethical approval for reporting individual cases or case series.

Consent for publication

Informed consent to publish has been obtained.

Competing interests

The authors declare no competing interests.