Heparin-induced thrombocytopenia syndrome as a cause of flap failure: A report of two cases

Case reports 

Case 1 

A 45-year-old woman with recurrent breast cancer underwent a complete skin-sparing mastectomy followed by immediate breast reconstruction using a contralateral pedicled transverse rectus abdominis myocutaneous (TRAM) flap. She had previously had a partial mastectomy and had received chemotherapy as well as radiotherapy. There was no history of a co-morbid disease and the patient was a non-smoker. Her preoperative laboratory parameters, including a coagulation profile, were all within normal limits. The preoperative platelet count was 202 000/μL. Her history did not reveal any previous exposure to heparin. Following an uneventful operation, the immediate postoperative flap was clinically well, warm, with a normal colour and capillary refill. There was no indication of vascular compromise. Thromboembolism prophylaxis included antithrombotic compression stockings and 5000 international units of unfractioned heparin given subcutaneously every 12h. Approximately 26h following surgery, the patient's pedicled flap began to show signs of venous congestion in a small well-delineated region (3×4cm) in the most distal aspect of the flap (zone II transverse rectus abdominis myocutaneous flap). Obvious signs of mechanical compression and infection were ruled out clinically and radiologically. Several sutures were removed to ensure there was no tension on the pedicle. Heparinised gauzes were applied regularly (every 1–2h) on to the compromised region. With the persistent venous congestion increasing slowly (5×8cm) on postoperative day 5, decongestion with medicinal leeches was started in the area of the congestion for a total of 3 days. The flap evolved favourably, with significant improvement in the previously congested region. The patient was discharged on postoperative day 8 with a small zone of questionable viability (3×5cm) which was treated conservatively. Two days following discharge, the patient presented to the hospital emergency department with a constellation of symptoms including nausea, vomiting, diarrhoea, hypotension, tachycardia and fever. The flap demonstrated increased evidence of congestion. On history, the change in the flap occurred within a 12–15h period prior to the emergency room visit. Following stabilisation the patient was transferred to the surgical intensive care unit for intensive monitoring and further work up. CT scanning demonstrated evidence of bilateral multiple small emboli. A heparin perfusion was started (25 000 units in 250cc of dextrose 5% at 10cc/h). On postoperative day 12, the patient's platelet count had dropped to 21 000/μL (from 142 000/μL) indicating severe thrombocytopenia (Fig. 1). Following evaluation, a diagnosis of HIT was entertained and consequently confirmed with a positive anti-heparin antibody assay. Heparin was discontinued and argatroban treatment was started. Following normalisation of her parameters and once fully anticoagulated, the patient was discharged from the hospital. Upon discharge, the platelet count had increased to 388 000/μL. On follow up 4 days later, the patient presented a new complaint of left lower extremity pain and was diagnosed with a new deep vein thrombosis (DVT). Her international normalised ratio (INR) was found to be nontherapeutic at 1.7. Following the resolution of her symptoms, she was discharged and re-admitted on postoperative day 30 for resection and debridement of her now well-demarcated necrotic flap (Figure 2, Figure 3, Figure 4). Pathological studies demonstrated a thrombosis of the flap vascular pedicle with complete luminal occlusion of both artery and vein (Fig. 5). The patient went on to heal without recurrence of any thromboembolic event. Her wounds healed uneventfully following discharge.

View Large Image Download to PowerPoint

Figure 1 Platelet count distribution over time.

View Large Image Download to PowerPoint

Figure 2 Demarcated necrosis of partially failed pedicled flap of the left breast.

View Large Image Download to PowerPoint

Figure 3 Failed flap after resection.

View Large Image Download to PowerPoint

Figure 4 Portion of vascular anastomosis with intraluminal thrombus.

View Large Image Download to PowerPoint

Figure 5 Thrombus in vascular lumen: artery and vein.

Case 2 

A 65-year-old man with known heavy alcohol and tobacco use underwent a floor-of-mouth and partial tongue resection followed by immediate reconstructive surgery with an osteocutaneous radial forearm free flap for an infiltrating squamous cell carcinoma of the inferior lip and mandible. Co-morbid factors included hypertension, hypercholesterolaemia and hypothyroidism. The patient's preoperative platelet count was 143 000/μL. His blood tests demonstrated a normal coagulation profile and mild pancytopenia. Postoperatively, the patient was given ASA (acetylsalicylic acid, 80mg po, daily), as well as heparin (5000 international units subcutaneously every 12h). Although pharmacologic measures were taken to prevent alcohol withdrawal, the patient experienced episodes of agitation, and combativeness on postoperative day 1. As the patient's aggressive behaviour increased, medications were administered to calm him; however, the patient went into respiratory depression leading to haemodynamic collapse.11 On postoperative day 2, following his stabilisation, venous congestion was observed on the flap and the patient was returned to the operating room for exploration of the anastomosis. A thrombectomy of the right external jugular vein with revision of the anastomosis was undertaken. An intravenous (i.v.) heparin perfusion was started. Approximately 24h following the second surgery, venous congestion recurred and the patient was taken back to the operating room for a second exploration. The patient underwent another thrombectomy and venous anastomosis revision. The patient was given 6000 international units of heparin perioperatively. On postoperative day 7, a return to the operating room was necessary due, once again, to recurrent venous congestion, and evidence of a complete thrombosis of the right external jugular vein was observed. Re-anastomosis was performed to the contralateral external jugular vein with an interposition vein graft. The patient received a total of 6000 units of heparin perioperatively. Following a final episode of venous congestion, medicinal leech therapy was started on postoperative day 8 (10-day treatment in total) (Fig. 6). On postoperative day 11 the patient was diagnosed with right lower extremity deep vein thrombosis and his platelet count had dropped to 26 000/μL (from 188 000/μL 4 days prior) (Fig. 7). Heparin was immediately discontinued and danaparoid sodium (Orgaran) was initiated (total use of 17 days). HIT was confirmed by a positive anti-heparin antibody assay. Platelet levels raised steadily after heparin was discontinued (Fig. 8). The patient's flap went on to heal following a successful course of leech therapy.

View Large Image Download to PowerPoint

Figure 6 Hirudinotherapy for venous drainage of recurrent venous thrombosis.

View Large Image Download to PowerPoint

Figure 7 Platelet count distribution over time.

View Large Image Download to PowerPoint

Figure 8 Follow-up picture 4 weeks following surgery.

Discussion 

Total vascular flap failure is an increasingly rare event as experienced centres emerge. Venous insufficiency can be identified by careful monitoring for signs of congestion, oedema, brisk and rapid capillary refill and a change in flap colour to darker red.12 Arterial thrombosis, although less frequent, can also be the cause of flap failure. Arterial insufficiency should be suspected when the flap is pale, cold, nonturgescent, lacks bleeding and when there is loss of arterial sign.12

When confronted with vascular thrombosis, each component of Virchow's triad should be evaluated in order to identify a reversible aetiology: stasis, hypercoagulability and vascular injury. Attempts should be undertaken to rule out causes of flap failure within these main three categories. Thrombosis risk factors need to be considered and can be classified within Virchow's triad (Table 1).4 When clinical signs of compromise become evident, immediate action is required for flap salvage. As a result, standardised postoperative flap surveillance plays a key role in early identification of complications. Patients should be returned for exploration of the anastomosis as soon as possible, looking for kinking, compression or thrombosis of the pedicle. Pharmacological interventions are co-players in attempting flap salvage. The mainstays of treatment are aspirin, heparin and dextran.5 Heparin is administered for its antithrombotic effects for both arterial and venous thrombi. Heparin can be given subcutaneously, i.v., or by topical application. Finally, the surgeon may use hirudinotherapy or leech therapy. Serletti et al. suggest intraoperative urokinase infusion set up to treat thrombus formation.3, 13

Table 1. Risk factors for thrombosis according to Virchow's triad

	Stasis	•Postoperative hypotension •Low intravascular volume •Vessel spasm •Pedicle tension, torsion, compression •Blood viscosity •Immobilisation •Obesity
	Hypercoagulable state	•HIT syndrome •Neoplasm •Pregnancy and post-partum •Hormone replacement therapy, oral contraceptives •Previous history of DVT, pulmonary embolism •Abnormal proteins C or S; factor V Leiden; abnormal factors (VIII, IX, X) •Antiphospholipid antibody syndrome
	Vascular injury	•Vessel dissection •Manipulation •Anastomosis •Recent trauma •Infection •Smoking •Diabetes

Ref. 21.

In both cases presented, the patients received heparin and postoperatively showed rapid signs of flap venous congestion. The flaps were carefully and regularly monitored for proper vascularisation. Each was treated to keep the flap viable. In the first case, heparin, heparinised gauzes and hirudinotherapy were used after excluding surgically treatable causes. In the second case, heparin, repeated thrombectomy/anastomosis revision and hirudinotherapy were used. Both cases were complicated by serious thrombocytopenia, flap pedicle thrombosis and life-threatening thromboembolic events.

When using heparin, the most frequently occurring complication is bleeding. However, these cases highlight another complication of heparin treatment, immune-mediated heparin-induced thrombocytopenia syndrome (HIT type II) resulting in a thrombogenic paradoxical state. Although patients suffer from severe thrombocytopenia (<100 000/μL or decrease by 50% of baseline), bleeding rarely occurs with HIT type II. Heparin, complexed to platelet factor 4, leads to antibody formation (heparin-associated anti-platelet antibodies, HAAb) with subsequent platelet activation and aggregation.9 The antibodies also activate vascular endothelium which results in the release of tissue factor. Incidence of thrombosis in HIT is 25–75% and is most frequently venous (4:1 venous to arterial ratio).14, 15 Postoperative patients are at greater risk because of endothelial wall damage with resultant increased platelet factor 4 and platelet activation. The risk of thrombosis can be present with a normal platelet count and up to 1 month after HIT has been diagnosed.7 Case 1 illustrates this increased risk as the patient suffered from a DVT 27 days after the initial surgery at a time when her platelet count was normal and the patient was under warfarin (Coumadin) therapy (although nontherapeutic, INR 1.7).

HIT type II should be clinically suspected when thrombocytopenia is documented following heparin therapy and when signs of arterial or venous thromboembolism are present (i.e. DVT, pulmonary embolism, stroke, limb ischaemia, mesenteric ischaemia, cerebral venous thrombosis, adrenal haemorrhagic infarction).10, 16 Acute HIT may develop in patients treated with heparin and recently exposed to the medication (within approximately 100 days). Previous heparin exposure should therefore be thoroughly documented.

The cases presented illustrate that HIT type II can be the cause of flap failure. If a patient has received heparin, HIT syndrome should be considered when other causes of microvessel thrombosis and thrombocytopenia have been ruled out. HIT can be confirmed when resolution of thrombocytopenia occurs after heparin has been discontinued and when anti-heparin antibodies are detected. Methods to diagnose HIT type II include functional assays (C-serotonin release and platelet aggregation) or immunologic assays (negative ELISA).17 Careful monitoring of platelet count is important if patients receive heparin (minimum of twice weekly).8 When HIT type II has been diagnosed, all heparin therapy must be terminated. This procedure is usually not sufficient to prevent further thromboembolic events as the cumulative frequency of HIT-associated thrombosis is approximately 50%, 30 days after cessation of heparin.18 Treatment therefore requires alternative anticoagulation therapy. In our cases, danaparoid sodium (Orgaran), a specific inhibitor of the Xa level of the coagulation cascade, and argatroban, a synthetic thrombin inhibitor derived from l-arginine were initially used until thrombocytopenia was resolved.19 Warfarin was then started and finally danaparoid sodium/argatroban discontinued once warfarin levels were therapeutic.

In both cases, the flaps demonstrated signs of venous congestion prior to clinical evidence of thromboembolism. This fact may suggest that unexplained flap venous thrombosis could be an early marker of thrombophilic states such as HIT syndrome. Indeed, the additional trauma to the flap vessels from dissection and micro-anastomosis could explain why thrombosis of those vessels occurs before major events such as DVT take place. Early recognition of the possibility of HIT syndrome will allow appropriate changes to be made to the treatment plan and therefore will decrease the risk of developing further life-threatening complications.

If heparin is required for patient treatment, the use of low-molecular weight heparin (LMWH) is favoured to minimise the risk of HIT syndrome as LMWH is less likely to trigger development of heparin-directed immune complexes. LMWH also has the advantage of a decreased bleeding risk, whilst being as effective as unfractioned heparin.20 Previous exposure to heparin needs to be thoroughly documented. Initially, a baseline platelet count should be noted and then monitored twice weekly. If there is any suspicion of HIT syndrome, heparin should be stopped and diagnosis may be confirmed with an anti-heparin antibody assay.

In conclusion, heparin-induced thrombocytopenia type II is a severe complication of heparin therapy. It can be the cause of severe thromboembolic events. Therefore, HIT type II may also be the cause of free flap as well as pedicled flap failure and should be considered early on when venous flap congestion is observed postoperatively. Practitioners should be alert for such an aetiology when confronted with recurrent unexplained venous thrombosis in a patient receiving heparin therapy.