Multiple Embolic Events in a Patient With Heparin Induced Thrombocytopaenic Thrombotic Syndrome and Mural Thrombus

SUMMARY

This report describes a 55-year-old man admitted for renal colic and found to have an infarcted right kidney, for which he was treated with heparin. Heparinization for this condition was stopped on day 12 when the patient developed pain in his left foot. Heparin- induced thrombocytopaenic thrombotic syndrome was confirmed, and despite treatment with danaparoid and bilateral femoral embolectomy, a left above-knee amputation was required. Echocardiogram showed a sessile mural thrombus in the left ventricle, which was considered a likely embolic source. The preoperative development of acute renal failure delayed recovery and necessitated haemodialysis. Anticoagulation of the patient was complicated; however, warfarin was introduced slowly and with good effect.

Key Words: SYNDROME, HEPARIN-INDUCED THROMBOCYTOPAENIA: renal infarct, mural thrombus, danaparoid

CASE HISTORY

A 55-year-old man presented to the Emergency Department with right flank pain and after treatment the patient was discharged with a diagnosis of renal colic, and an outpatient booking for a spiral CT.

Spiral CT showed a 5 mm calculus in the lower aspect of the left kidney and a 5 mm calculus in the lower pole of the right kidney.

The patient represented seven days later with recurrent right flank pain, radiating to his groin and resistant to pethidine, indomethacin, metoclopramide and hyoscine. Urine analysis was negative for blood or protein; blood urea was 9.3 mol/l and creatinine 139 mol/l. A renal CT angiogram again showed calculi in the right and left renal pelvices. There was no evidence of ureteric calculi, hydronephrosis or renal vein changes. The right kidney appeared infarcted.

On Day 1 of admission the patient was transferred to the High Dependency Unit (HDU) and heparinized with a 2500 U bolus injection and an infusion of 10,000 units of heparin in 100 ml of normal saline, initially at 10 ml/h. The infusion was titrated according to the activated partial thromboplastin time (APTT) with a target of 60 to 80 seconds (normal range: 22 to 35 seconds).

The next morning a renal duplex ultrasound revealed a swollen right kidney 12.1 cm x 5.5 cm, the left being 9.7 5.5 cm. The main right renal artery waveform was unobtainable, and likewise the intrarenal waveform showed the presence of oscillating flow, consistent with very low perfusion pressure and confirming infarction of the right kidney. A vascular surgeon reviewed the patient and a preliminary diagnosis of renal artery thrombosis was considered more likely than a dissection, given no history of previous vascular surgery. Remedial surgery, angiography and lysis were considered, but it was thought to be too late, and heparin was continued with a planned repeat renal angiogram in one week. Stenting would then be performed if the kidney had evidence of perfusion.

On day 12 post-admission the patient developed severe left leg pain. The limb was numb and cold to touch, with purple discolouration of toes 4 and 5 on the left foot being noted. The patient’s right leg was also cool below the knee. The platelet count was 97 10^sup 9^/l, reduced from 276 10^sup 9^/l, on day 2 (Figure 1). The patient was sent to the operating theatre urgently and a bilateral femoral embolectomy performed showed microvascular thrombus with a larger arterial thrombus in the left leg.

Histology of the blood clot from the left femoral artery showed two irregular fragments, the larger one 60 10 3 mm and the second 30 5 3 mm. The histology confirmed the presence of thrombus and no evidence of malignancy. A heparin-induced thrombocytopaenic thrombotic syndrome (HITTS) screen was performed for heparin, enoxaparin sodium, dalteparin sodium and heparinoid antibodies, using the hospital’s drug samples. The patient was found to be negative only for heparinoid antibodies. The heparin infusion was ceased (day 12 post-admission) and a danaparoid bolus of 2500 IU was given and infusion started at 400 IU/h for four hours followed by 300IU/h for four hours. The patient’s anti Xa levels were checked pre-dose and throughout the danaparoid infusion, with the titration aiming for anti Xa levels of 0.5 to 0.8 IU.

FIGURE 1: The patient’s platelet count fell with time of exposure to heparin, and the patient developed symptoms of HITTS on day 12 post-admission (heparinization was initiated on day 1 and ceased on day 12).

On Day 13 of admission a transthoracic echocardiogram was done to exclude an embolic source for the clots. This showed a 52 23 mm extensive, mobile apical cardiac thrombus. A repeat bedside transthoracic echocardiogram on day 27 showed no significant alteration in the thrombus (Figure 2).

On Day 13 a central venous double-lumen catheter (Vascath Kendall, New Jersey, U.S.A.) was inserted into the right internal jugular for continuous venovenous haemodiafiltration (CVVHF). At that time the patient had a potassium of 5.4 mmol/l, creatinine 540 mol/l, WCC 30.2 10^sup 9^/l, platelets 64 10^sup 9^/l, creatine kinase 1200 (normal range 0-180 IU/l), anti Xa 1.23 IU (normal range: 0.5 IU) and no evidence of myoglobinuria.

Clotting of the dialysis circuit occurred six times over the next three days. This was improved by placing the danaparoid syringe on the same line as the Prisma M100 filter (Gambro, Sydney, Aust.), rather than as a separate IV infusion, and run at the same rate of 6 ml/h, titrated according to the anti Xa levels. A diethylene triamine penta-acetic acid (DTPA) scan was done on day 20 to investigate renal perfusion. It showed a mild delay to the left kidney, but otherwise perfusion was preserved. The patient had stabilized enough to proceed with the left above-knee amputation, and further delay was not possible because the patient’s leg was beginning to mummify. After full discussion of the risks with the patient and his family a left above-knee amputation was performed. The patient’s recovery was slow and on day 21 post-admission warfarinization was commenced at 5 mg daily and monitored (INR 1.9- 3.4). Phantom limb pain was treated successfully with gabapentin 200 mg daily. The patient developed dull left upper arm pain on day 29 post-admission. Fortunately the pain resolved spontaneously after twenty minutes and an urgent upper limb ultrasound showed no obvious emboli. The patient was transferred to the ward on day 48 and, after rehabilitation, went home on day 78.

FIGURE 2: Transthoracic echocardiogram on Day 27 showing an extensive mobile apical cardiac thrombus, considered a possible embolic source.

DISCUSSION

HITTS is a condition that results in paradoxical venous or arterial thrombosis during anticoagulation therapy, and typically develops seven to twelve days after commencing heparin anticoagulation12. It can develop as quickly as 10 hours after initiation of heparin therapy if the patient has had prior exposure to heparin3. This rapid response can be triggered up to 100 days after heparin exposure. HITTS is reported to develop in 3% of all patients treated with unfractionated heparin4.

The patient developed a renal infarct prior to being exposed to heparin, and as such the initial embolus was presumed to be of cardiac origin. The patient may then have had further emboli to his femoral arteries or arterial thrombosis secondary to HITTS.

Warkentin et al5 reviewed 158 patients with HITTS, ten of whom developed arterial occlusion. In their experience the seven patients who underwent thrombectomy and limb salvage survived, whilst all three patients who required limb amputation died. They also noted that patients who had deep venous thrombosis and HITTS were surprisingly more likely to develop venous limb gangrene after excessive anticoagulation with warfarin (8/8 with median INR 5.8 compared to 3/8 with median INR 3.1). There was no evidence that this patient had venous gangrene, however we do not know of a trial of warfarin and heparinoid therapy for patients with serologically confirmed HITTS, arterial limb gangrene resistant to embolectomy and a mural thrombus. The ratio of venous thrombosis to arterial thrombosis in confirmed HITTS cases is between 3 and 4:1(6,7).

Our patient was commenced on warfarin on day 21 post-admission, starting with Smg/day and monitored (INR 1.9-3.4) to avoid the possibility of increased risks of clotting as seen in limited study of venous limb gangrene patients who were excessively anticoagulated (INR 5.8-7.9). We also waited for the patient’s platelet count to recover with danaparoid sodium before commencing warfarin. Work by the Australian Heparin-induced Thrombocytopaenia Study Group3 has shown the heparinoid, danaparoid sodium to be safe and effective when used with warfarin for the treatment of heparin-induced thromboctopaenia with thrombosis.

A study by Warkentin and Kelton7 reported 127 patients with heparin-induced thrombocytopaenia over a fourteen-year period. They noted that approximately half the heparin-induced thrombocytopaenia patients were identified only after they had a thrombotic event. The other 62 patients who were identified with heparin-induced thrombocytopaenia had a subsequent 30-day risk of thrombosis of 52.8%. This highlights the importance of being vigilant for heparin- induced thrombocytopaenia but the difficulty of avoiding the subsequent thrombotic events. In that study, 78 patients had venous thrombotic eventscompared to only 18 patients with arterial occlusions.

Interestingly the patient’s right leg perfusion improved after the left leg above-knee amputation and the patient’s renal function improved by the time of discharge. Further trials of anticoagulation therapy would help guide the treatment of patients with this constellation of pathologies, but may be difficult to conduct.

ACKNOWLEDGMENTS

We would like to acknowledge Dr Kelleher, the Director of Cardiology at Bankstown-Lidcombe Hospital for his assistance.

REFERENCES

1. Ballard GO, Anticoagulant-induced thrombosis. JAMA 1999; 282:310-312.

2. Warkentin TE, Levine MN, Hirsh J et al. Heparin-induced thromhocytopaenia in patients treated with low-molecular-weight- heparin or unfractionated heparin. N Engl J Med 1995; 332:1330- 1335.

3. Chong BH, Gallus AS, Cade JF et al. Australian HIT Study Group. Prospective open-label comparison of danaparoid with Dextran70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost 2001; 86:1170- 1175.

4. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopaenia. N Engl J Med 2001; 344:1286-1292.

5. Warkentin TE, Elavathil LJ, Hayward CP, Johnston MA, Russell JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin- induced thrombocytopaenia. Ann Intern Med 1997; 127:804-812.

6. Magnani HN. Heparin-induced thrombocytopaenia (HIT): An overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70:554-561.

7. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopaenia. Am J Med 1996; 101:502-507.

G. BENNETT*, M. R. HANLEY[dagger]

Intensive Care Unit, Bankstown-Lidcombe Hospital, Sydney, New South Wales

* F.A.N.Z.C.A., M.B.B.S., Director.

[dagger] M.B.B.S.(Qld), B.Sc.(Syd.), Resident in Intensive Care.

Address for reprints: Dr M. Hanley, 3/33 Lidbury St, Berala, N.S.W. 2141.

Accepted for publication on August 19, 2004.

Copyright Australian Society of Anaesthetists Dec 2004