Management of patients with heparin-associated thrombocytopenia and thrombosis requiring cardiac surgery

Heparin-associated thrombocytopenia and thrombosis (HATT) is a serious complication of heparin therapy that results in intravascular platelet aggregation with arterial or venous thrombosis. Platelet aggregation to heparin in vitro is used to confirm the diagnosis. Cessation of heparin therapy with avoidance of reexposure to heparin is an important principle in the management of HATT. However, certain patients with HATT may require reexposure to heparin for emergency cardiac operations requiring cardiopulmonary bypass while still demonstrating positive in vitro platelet aggregation with heparin. The present report describes the management of 2 such patients. In each patient aspirin was shown to inhibit platelet aggregation to heparin in vitro; therefore, aspirin and dipyridamole were administered to each patient before heparin reexposure and continued throughout the perioperative period. Cardiopulmonary bypass with full heparinization was achieved without thrombotic or hemorrhagic complications in both patients. Despite the presence of a heparin-dependent platelet-aggregating factor in the plasma of these 2 patients, inhibition of platelet aggregation with aspirin and dipyridamole allowed uneventful reexposure to heparin.     

The effect of thromboxane receptor blockade versus thromboxane synthase inhibition on canine arterial graft patency

This study compared the effects of a thromboxane synthase inhibitor, thromboxane receptor antagonist, and cyclooxygenase inhibitor in a canine arterial graft patency model. Fifty-six dogs were divided into a control (no treatment) and five treatment groups: thromboxane synthase inhibitor (U63557A; 15 mg/kg/tid); thromboxane receptor antagonist (SQ29548; 0.02 mg/kg/hr); high-dose aspirin (325 mg/day; low-dose aspirin (1 mg/kd/day; and aspirin plus dipyridamole (325 mg/day aspirin; 3 mg/kg/day dipyridamole). Drugs were orally administered except for thromboxane receptor antagonist, which was delivered intravenously by minosmotic pumps. After 24 hours of drug treatment, bilateral femoral artery prosthetic grafts (4 mm diameter x 7 cm; 1 polytetrafluoroethylene and 1 Dacron) were implanted. Patency was determined after 1 week. Dogs were classified before operation according to their epinephrine-enhanced arachidonate-stimulated platelet aggregation response. Polytetrafluoroethylene and Dacron graft patency rates were equivalent in all groups. Overall graft patency was significantly improved from 42% (control) to 94% by both high-dose aspirin and thromboxane receptor antagonist (p less than 0.001). Aspirin-dipyridamole also improved patency (83%; p less than 0.01 versus control), whereas thromboxane synthase inhibitor and low-dose aspirin were not effective. Baseline platelet aggregation was not predictive of patency. The drugs that promoted graft patency in this model either suppressed both thromboxane A2 and prostaglandin H2 formation (high-dose aspirin) or blocked their combined platelet receptor (thromboxane receptor antagonist). Thromboxane synthase inhibitor may be ineffective because prostaglandin H2 production is allowed. These data suggest that activation of the platelet thromboxane A2-prostaglandin H2 receptor is an essential event in early arterial graft thrombosis.     

Early healing after carotid endarterectomy: effect of high- and low-dose aspirin on thrombosis and early neointimal hyperplasia in a nonhuman primate model

Platelet aggregation and release phenomena are central to most postulated mechanisms of thrombosis and neointimal hyperplasia after carotid endarterectomy. Therefore high-dose aspirin (HDA) has been advocated to minimize these sources of endarterectomy failure. We have defined low-dose aspirin (LDA) that selectively blocks platelet cyclooxygenase but preserves arterial wall cyclooxygenase in the nonhuman primate, Macaca fascicularis. We compared this theoretically optimal aspirin dose with HDA and no treatment (control) in a model of carotid endarterectomy. The aspirin was started before operation and continued for 6 weeks after operation, at which time the endarterectomized vessels were excised. The patency and morphologic findings of the arteries were measured. Platelet function was monitored by bleeding time and serum thromboxane A2 determinations. LDA and HDA were associated with 100% patency, whereas the control group had 50% patency. However, HDA did not protect the vessel from developing neointimal hyperplasia, which was seen in the control group and was associated with platelet adherence to the flow surface at 6 weeks. At 6 weeks, LDA significantly decreased but did not totally prevent neointimal hyperplasia and the flow surface was healed. Therefore the genesis of neointimal hyperplasia after endarterectomy may be more complex than simply a function of platelet-vessel wall interaction.     

Experimental models for evaluating antithrombotic therapies in replantation microsurgery

A variety of anticoagulation and antiplatelet aggregation agents are in use clinically, and in applications to microvascular surgery, a clear choice for the most effective therapy has not been determined. Models of vascular trauma combined with microvascular anastomosis have been developed for comparing the efficacy of these agents in maintaining vascular patency. In a rat model of microvascular thrombosis, heparin effectively prevents occlusion in both arteries and veins, at clinical levels of administration. Aspirin helps prevent thrombosis, but not as well as heparin. These results support the beneficial effect of antithrombotic drug therapies, and suggest a more potent role of the heparin-inhibited fibrin clot over platelet aggregation in creating thrombotic occlusion of small vessels.     

Heparin-associated thrombocytopenia and thrombosis: a serious clinical problem and potential solution

Heparin-associated thrombocytopenia and thrombosis (HATT) is an unusual but serious complication of heparin therapy. Twenty-five patients (13 men and 12 women) had thrombocytopenia and arterial or venous thrombosis 1 to 10 days (mean, 6.3 days) after the start of heparin administration. The vessels in the affected extremity had been entered for catheterization, arteriography, or passage of a balloon counterpulsation device in 19 of the 25 patients. In vitro platelet aggregation with heparin was seen in all patients. Additional studies were performed to see whether other lots or sources of heparin also produced in vitro aggregation. Four separate lots of beef lung heparin, commercial heparin from porcine intestinal mucosa, and two types of low molecular weight heparin were all highly stimulatory in this system. However, Org 10172, a heparinoid, did not induce aggregation in any of 13 patient plasmas tested. Inhibition of platelet aggregation by aspirin was also examined. Aspirin abolished in vitro aggregation in 9 of 16 cases and decreased the degree of aggregation from 85% to 55% (p = 0.02) in the remaining seven cases. We conclude that in patients with HATT platelet aggregation is equally induced by beef lung, porcine intestinal, and some forms of low molecular weight heparin. Org 10172 does not stimulate platelet aggregation in plasma from these patients in vitro. Finally, there may be a role for aspirin in treating patients with HATT.     

Effect of preoperative antiplatelet drugs on vascular prostacyclin synthesis

Patients undergoing aortocoronary bypass using autogenous saphenous veins were randomly divided into three comparable groups. Group 1 (n = 10) acted as a control, Group 2 (n = 14) received 80 mg of aspirin at midnight before the operation, and Group 3 (n = 12) received 80 mg of aspirin and 75 mg of dipyridamole at midnight and an additional 75-mg dose of dipyridamole at 6 AM. The purpose was to determine which regimen would maximally inhibit platelet function without depressing vascular prostacyclin synthesis. Serum thromboxane A2, saphenous vein wall and aortic wall prostacyclin, platelet aggregation, and bleeding time were measured in all patients. None was restarted on a regimen of aspirin or dipyridamole postoperatively. Aspirin alone and in combination with dipyridamole significantly inhibited thromboxane A2 and platelet aggregation in all treated patients but spared venous prostacyclin synthesis. Aortic prostacyclin synthesis was partially inhibited in both treated groups. Chest tube drainage was comparable in all three groups. These results indicate that the combination of aspirin and dipyridamole offers no measurable advantage over aspirin alone in the perioperative period.     

Platelet aggregation inhibition in human umbilical vein grafts and negatively charged bovine heterografts.

Glutaraldehye-tanned human umbilical vein grafts (4 mm) and negatively charged bovine heterografts (4 mm) were placed as bypasses in the femoral arteries of 20 dogs randomized into 10 treated with aspirin and dipyridamole and 10 were not treated. Autogenous vein grafts were placed as controls. Platelet aggregation inhibition by aspirin and dipyridamole significantly improved the patency of human umbilical vein grafts from 10% to 60%. It had no effect on patencies of autogenous veins (100%) or on negatively charged bovine heterografts (0% patency). Inherent graft properties continue to play an important and sometimes overriding role in long-term graft patency in small vessel bypasses. Neointimal fibrous hyperplasia at both proximal and distal anastomoses again was shown to be intimately associated with late graft occlusions.     

The effect of twisting on microanastomotic patency of arteries and veins in a rat model.

The authors examined the effect of twisting on the patency of microvascular anastomoses 3 days after surgery. A total of 69 male Wistar rats were divided randomly into four groups. The femoral arteries and veins were dissected for a standard distance. A total of 69 microarteriorrhaphies and 68 microvenorrhaphies were performed at 0 deg and with twist of the vessel ends of 90, 180, and 270 deg. Three-day patency rates for arterial microanastomoses were 100% with a 0-deg twist, 80.9% with a 90-deg twist, 68.4% with a 180-deg twist, and 64.2% with a 270-deg twist. Three-day patency rates for venous microanastomoses were 100% with a 0-deg twist, 85% with a 90-deg twist, 28.5% with a 180-deg twist, and 25% with a 270-deg twist (p = 0.047 for arteries, p = 0.001 for veins). These data are statistically significant. Moreover, assuming the risk of thrombosis to be 1 for microanastomosis without twisting, the odds ratio for the risk of vessel thrombosis for 270-deg twisting (the maximal examined degree of arterial and venous twist in the current study) is 10.08 for arterial anastomosis and 226.85 for venous anastomosis.     

Comparison of single-dose antithrombotic agents in the prevention of microvascular thrombosis.

A model of thrombosis was used to evaluate the efficacy of single-dose heparin, hemodilution, and 40,000 milliwatts dextran in the prevention of microvascular thrombosis. Forty Lewis rats (275 gm body weight) were divided into four groups (n = 10): hemodilution (6 ml NS), single-dose heparin (1 mu/gm), 40,000 mw dextran (0.3 gm/100 gm), and control (0.275 ml NS). After exposure of the superficial femoral arteries, a model of arterial crush with arteriotomy followed by an intimal abrasion was used. The animals randomly received one of the four solutions above. Experimental results included patency rates of 90% at 20 minutes and 10% at 24 hours in the hemodilution group, 100% at 20 minutes, and 70% at 24 hours in the single-dose heparin group, and 100% at both 20 minutes and 24 hours in the dextran group. A 100% thrombosis rate was observed in the control group at 20 minutes and 24 hours. Single-dose heparin and dextran significantly improved patency in comparison to both the control and hemodilution groups at 24 hours (p less than 0.01). Scanning electron microscopy of the vessels revealed thrombus deposition consistent with these findings. These results indicate that single-dose heparin and single-dose dextran reduce thrombosis in this model of microvascular injury.     

Oral acetylsalicylic acid improves patency rates in small-vessel anastomoses

Because platelet aggregation is the critical step in vascular thrombosis, this study investigated the possibility that acetylsalicylic acid given orally would improve patency of anastomoses in small arteries. Under clean conditions, in male Sprague-Dawley rats, the superficial femoral arteries were divided and reanastomosed using the sleeve technique with 10-0 nylon suture. Fifty-one rats received a full laboratory diet and acetylsalicylic acid in their drinking water (1.08 mg/ml), before and after operation. A control group of 54 rats was matched for weight, water intake and duration of vessel occlusion. Vessel patency was assessed on postoperative day 7, at sacrifice, by dye angiography. In the experimental group 7 (13.7%) anastomoses became occluded, compared with 20 (37.0%) in the control group (chi 2 = 5.99, df = 1, p less than 0.025). Serum thromboxane B2 levels in five rats given acetylsalicylic acid orally (33.1 +/- 6.1 ng/ml) were significantly (p less than 0.001) lower than in five control rats (86.6 +/- 49.1 ng/ml). The authors concluded that acetylsalicylic acid administered in the drinking water to Sprague-Dawley rats improved the patency rate of femoral artery anastomoses probably because of a reduction in platelet aggregation. Orally administered acetylsalicylic acid may be of clinical benefit to patients who undergo small-vessel anastomoses.     

Low-dose aspirin protects against lipid accumulation in primate vein bypass grafts

Platelet inhibition with high-dose aspirin combined with dipyridamole reduces lipid accumulation and improves early patency of coronary artery bypass grafts. However, recent evidence suggests that platelet inhibition can be achieved with substantially lower aspirin doses than have been conventionally prescribed. To evaluate whether low-dose aspirin protects against lipid accumulation in bypass grafts, we studied 15 stump-tailed macaque monkeys in which autologous cephalic veins were grafted into the femoral arteries. A control group received no treatment, a second group was treated with a low, single daily dose of aspirin (12 mg), and a third group was given a higher dosage of aspirin (80 mg/day) combined with dipyridamole (50 mg/day) divided into two daily doses. A special diet was fed that resulted in plasma cholesterol levels (224 +/- 50 mg/dl, mean +/- standard deviation) and plasma lipoprotein distributions that mimic the profile in humans. Cholesterol concentration in grafts removed 3 months after insertion was 0.47 +/- 0.12 mg/100 mg tissue in the control group; it was reduced to 0.23 +/- 0.04 mg/100 mg (p less than 0.001) by low-dose aspirin and to 0.17 +/- 0.05 mg/100 mg (p less than 0.001) by combined aspirin and dipyridamole therapy. Graft apolipoprotein B concentration was 66 +/- 19 micrograms/100 mg in control group; it was reduced to 40 +/- 8 micrograms/100 mg (p less than 0.05) by low-dose aspirin and to 23 +/- 7 micrograms/100 mg (p less than 0.001) with the combination treatment. There were no differences between groups in either cholesterol concentration (0.09 +/- 0.02 mg/100 mg) or apolipoprotein B concentration (10 +/- 3 micrograms/100 mg) in normal ungrafted vein. Platelet function tests demonstrated platelet aggregation in all control monkeys, in none of the combined therapy group, and in two of five monkeys receiving low-dose aspirin. This study indicates that low-dose aspirin is protective against graft lipid accumulation in monkeys. The mechanism of this antilipid effect and its relation to any antithrombotic effect remain to be elucidated.     

Combined arachidonic acid and ADP platelet inhibition maximizes patency of small-diameter vascular grafts

Arachidonic acid (AA) and adenosine diphosphate (ADP) are potent stimuli of platelet aggregation. Each agonist may act through separate platelet pathways. In order to evaluate inhibition of ADP and AA on platelet aggregation, we studied the effect of ticlopidine (TC) and aspirin (ASA) alone and in combination on plasma thromboxane levels, platelet deposition, and patency of small-diameter vascular grafts in a canine model. Thirty-four mongrel dogs were classified as thrombosis prone (TP) or thrombosis resistant (TR) on the basis of in vitro platelet aggregation to AA. Four groups were studied: group I, control; group II, TC (100 mg/kg/day); group III, ASA (3 mg/kg/day); and group IV, TC/ASA (same doses). PTFE grafts were implanted bilaterally in the carotid and femoral arteries Ticlopidine inhibited in vitro platelet aggregation to both ADP and AA but had no significant effect on plasma thromboxane (Tx) B2 production. Aspirin inhibited AA-induced platelet aggregation and significantly decreased TxB2 production. Aspirin inhibited AA-induced platelet aggregation and significantly decreased TxB2 levels in both TP and TR animals (p less than 0.01). Although TC and ASA significantly inhibited platelet deposition and improved 1-month patency in both TP and TR animals, maximal patency was achieved in the group in which TC and ASA were combined. We conclude that platelet ADP and AA pathways are important determinants of the thrombogenic potential in vascular graft performance in dogs and that combined inhibition of both pathways achieves maximal vascular graft patency.     

Scanning electron microscopy of crush/avulsion arterial trauma:effect of heparin and aspirin administration

A model of vascular trauma and subsequent reanastomosis with poor postoperative likelihood of patency was developed in the rat femoral artery. Patency rates were significantly improved with intravenous heparin, intragastric aspirin, and both agents together. Heparin yielded higher patency than aspirin. Intimal surfaces of the vessels at various postoperative intervals were observed with the scanning electron microscope. More fibrin accumulation was seen in the aspirin-treated animals, while more platelet aggregation was found in the heparin-treated group. Both platelet aggregation and fibrin strand development appeared retarded with both agents administered. All groups demonstrated good healing of the ruptured intimal surfaces, beginning at 2 days postoperatively. It is concluded that fibrin strand development is a more significant factor in microvascular occlusion than platelet aggregation.     

Antithrombotic benefit of subendothelium-bound urokinase: an experimental study.

To improve the outcome of extremity replantation, microsurgeons have administered systemic antithrombotic agents (e.g., heparin, aspirin, dextran). To obviate the risks associated with systemic anticoagulation, we have investigated the use of topically applied urokinase for its binding capacity to arterial subendothelium and for its ability to prevent subsequent thrombosis. An arterial model of thrombosis associated with intimal deendothelialization was developed. Donor rat carotid arteries were everted and mechanically deendothelialized with a scalpel blade. The vessels were next subjected to one of several treatments, which included 30-minute incubation with urokinase, heparin, or vehicle (lactated Ringer's solution). The vessels were then washed, reinverted to normal orientation, sectioned into 5 mm lengths, and grafted into the femoral arteries of recipient rats. Two-hour patency rates were 25% for controls (n = 20), 10% for heparin-treated vessels (n = 10), and 55% for urokinase-treated vessels (n = 20); this last was significantly greater than the other two groups. In vitro investigations revealed that urokinase has a high capacity for binding to subendothelium, with a release half-life of approximately 20 minutes. Surface-bound urokinase was found to have proteolytic activity similar to that of urokinase in solution. These results indicate that urokinase may be a more beneficial irrigating solution additive than heparin for repair of traumatized vessels.     

尿激酶原基因防止静脉桥血栓形成的实验研究

目的 探讨尿激酶原基因对静脉桥血栓形成的影响。方法 取下大鼠颈静脉，两端阻断后，用含Ａｄｖ５－ＣＭＶ质粒（对照组）或含Ａｄｖ５－ＣＭＶ／Ｐｒｏ－ＵＫ质粒（治疗组）的溶液扩张静脉，使溶液在静脉腔内滞留３０分钟，然后植于同一大鼠的颈总动脉。术后１４天分别取对照组和治疗组的静脉移植物、纤维溶圈的方法测定尿激酶原活性，观察Ｐｒｏ－ＵＫ基因的表达。术后２４小时，取静脉桥测定标记血小板数。术后１４天，取移植静     

Carotid endarterectomy in patients with heparin-induced platelet activation: comparative efficacy of aspirin and iloprost (ZK36374)

Patients with heparin-induced platelet activation who are reexposed to heparin may have recurrent thrombocytopenia, intravascular thrombosis, arterial emboli, or sudden death. To permit carotid endarterectomy in two patients with confirmed heparin-induced platelet activation, we compared the efficacies of aspirin and iloprost, a stable analogue of prostacyclin, in preventing heparin-induced platelet activation. In the first patient, although aspirin prevented both in vitro heparin-induced platelet aggregation (70% without and 7.5% with aspirin) and 14C serotonin release (48% without and 0% with aspirin), intraoperative administration of heparin resulted in an increase in plasma levels of platelet factor 4 from 8 to 260 ng/ml and beta-thromboglobulin levels from 29 to 39 ng/ml. In addition, the circulating platelet count decreased from 221,000 to 174,000 microliters, and 15% spontaneous platelet aggregation was observed. Fortunately, fibrinopeptide A levels remained less than 10 ng/ml intraoperatively, and no thrombotic complications occurred. In the second patient, aspirin did not prevent heparin-induced platelet aggregation in vitro (65% without and 41% with aspirin); however, iloprost (0.01 mumol/L) prevented both in vitro heparin-induced platelet aggregation (59.5% without and 0.0% with iloprost) and 14C serotonin release (56.7% without and 0.0% with iloprost). Therefore, a continuous infusion of iloprost was begun before administration of heparin and was continued until 20 minutes after reversal of heparin with protamine. After intraoperative administration of heparin, plasma levels of platelet factor 4 increased from 19 to 200 ng/ml, and beta-thromboglobulin levels increased from 56 to 76 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-molecular-weight heparin exerts an early antithrombotic effect in small arteries and veins following severe trauma.

Administration of low-molecular-weight heparin (LMWH) and standard heparin was studied by evaluating vessel bleeding, patency, and thrombotic material following severe vascular trauma. Arteriotomy and intimectomy or venotomy and intimectomy were performed on small rabbit arteries or veins in two separate blinded studies. All vessels were closed using a continuous microvascular suture. Patency and weight of thrombotic materials were evaluated 2 hr after reperfusion. In the arterial study, two groups of 23-24 arteries were treated with saline or LMWH systemically. Bleeding times were 89 +/- 15 sec in the control group and 103 +/- 27 sec in the LMWH group; there was no significant difference between the groups. Patency was significantly increased in the LMWH group (79%) compared to the control group (52%). The weight of thrombotic material in the LMWH group (1.39 +/- 0.20 mg per artery) was significantly different compared to the control group (2.19 +/- 0.22 mg per artery). In the venous study, 65 veins were divided into three groups (21-23 vessels/group) and treated with systemic saline, heparin, or LMWH. Bleeding times in the conventional heparin group (37 +/- 7 sec), the control group (23 +/- 3 sec), and LMWH group (22 +/- 4 sec) were not significantly different. The patency rates were significantly increased in the heparin (42%) and LMWH (39%) groups compared to the control group (0%). The weight of thrombotic material in each vein was significantly less in the LMWH (1.07 +/- 0.24 mg) and heparin (1.78 +/- 0.52 mg) groups than in the control group (3.78 +/- 0.29 mg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Saratin, an inhibitor of von Willebrand factor-dependent platelet adhesion, decreases platelet aggregation and intimal hyperplasia in a rat carotid endarterectomy model.

PURPOSE: Post-carotid endarterectomy, thrombosis, and intimal hyperplasia may be decreased by the inhibition of platelet adhesion and activation. In this study, a novel agent, saratin, was used to inhibit platelet-to-collagen adhesion in a rat carotid endarterectomy model. Saratin is a recombinant protein isolated from the saliva of the medicinal leech Hirudo medicinalis, which is thought to act by binding to collagen, and inhibits von Willebrand factor-collagen interaction under conditions of increased shear and therefore, the adherence and activation of platelets at the vessel wall. Saratin has the advantage of being a nonsystemic, site-specific topical application. METHODS: A rat carotid endarterectomy model was used in which an open technique with arteriotomy and intimectomy was used. Saratin was applied to the endarterectomized surface of the carotid artery before arterial closure. End point measurements included platelet adhesion, thrombosis rate, intimal hyperplasia development, bleeding times, and platelet counts. Electron micrographs of carotid arteries were used for quantitative analysis of platelet aggregation and platelet counts. Intimal hyperplasia and thrombosis were assessed with computer-assisted morphometric analysis of elastin-stained carotid artery sections with direct measurement of the intimal hyperplasia area. RESULTS: The topical application of saratin significantly decreased platelet adhesion compared with controls at 3 hours after carotid endarterectomy (64 +/- 17 vs 155 +/- 33 platelets per grid, P = .05), and 24 hours after carotid endarterectomy (35 +/- 11 vs 149 +/- 37 platelets per grid, P = .0110), respectively. A percent luminal stenosis, as a measure of intimal hyperplasia, was significantly decreased with saratin application compared with controls (10.9% +/- 1.8% vs 29.8% +/- 6.8%, P = .0042). This decrease in intimal hyperplasia formation correlated with the inhibition of platelet adhesion. Thirty-three percent of control arteries were found to be thrombosed 2 weeks after carotid endarterectomy compared with a 0% thrombosis rate in the saratin-treated group (P = .0156). No increased bleeding was encountered along the arterial suture line in the saratin group. Bleeding times and systemic platelet counts were not found to change significantly in the saratin-treated rats compared with control rats at 3 and 24 hours after endarterectomy. CONCLUSION: Saratin significantly decreased platelet adhesion, intimal hyperplasia, luminal stenosis, and thrombosis after carotid endarterectomy in rats. Saratin did not increase suture line bleeding or bleeding times, and did not decrease platelet counts. Saratin may serve as a topical agent to be used for the site-specific inhibition of thrombosis and intimal hyperplasia after vascular manipulation.     

Effects of enoxaparin,standard heparin,and streptokinase on the patency of anastomoses in severely crushed arteries

The effects of topical irrigation with three antithrombotic agents on the patency of anastomosed arteries following crush injury were examined. Following an impact crush injury with a 25 kg crush load, the femoral arteries of rats were divided and then anastomosed. During anastomoses, the vessel lumina were topically irrigated with saline, streptokinase, standard heparin, or enoxaparin (a low molecular weight heparin). The results were evaluated by patency test and histology up to day 56. The thrombosis rate at days 1 and 7 was statistically lower (P<0.05) in the standard heparin and the enoxaparin groups than in the other two groups. The difference between the standard heparin and the enoxaparin groups was not statistically significant. Histology at day 1 showed that thrombus in the occluded vessels adhered to the exposed adventitia in the crushed area or the adventitia was covered by fibrin, red blood cells, and platelet mesh in the patent vessels. The results showed that 1) topical irrigation with standard heparin or enoxaparin solution significantly reduced the thrombosis rate at the anastomosis site of the crushed arteries; and 2) enoxaparin was as effective an antithrombotic agent as standard heparin when topically applied during microvascular anastomoses. © 1995 Wiley-Liss, Inc.     

Diagnostic and therapeutic strategies of white clot syndrome.

This study describes our experience with 12 patients with white clot syndrome encountered during a recent 36-month period. The diagnosis was based on the following criteria: (1) development of thrombocytopenia of less than 100,000/mm3 during administration of heparin therapy, (2) normalization of the platelet count after an interruption in heparin therapy, (3) exclusion of other causes of thrombocytopenia, (4) a positive heparin-induced platelet aggregation test, (5) detection of white clots on pathologic examination, and (6) the presence of thrombotic complications. Of 2,500 patients who received heparin therapy, 12 (0.48%) developed white clot syndrome. Various indications, routes of administration, and types of heparin were implicated. The mean platelet nadir was 26,900/mm3, and the mean time to onset of heparin-induced thrombocytopenia was 5 days. Thrombotic complications included arterial occlusions of the legs in 11 patients, deep vein thrombosis of the legs in 9 patients (4 had pulmonary embolism), and combined arterial and venous thrombosis in 8 patients. Treatment strategies included discontinuation of heparin in all patients and intravenous infusion of dextran, followed by arterial thrombectomy in four patients, urokinase therapy in two patients for arterial complications, and insertion of Greenfield filters in six patients. All patients were given warfarin. The mortality rate was 25% and the morbidity rate was 50%. An initial platelet count should be obtained on all patients prior to receiving heparin, followed by repeat platelet counts every 2 to 3 days. Once thrombocytopenia or thrombosis is diagnosed, heparin should be discontinued and other methods of therapy considered.