White Clot Research Articles

An overview of the heparin-induced thrombocytopenia syndrome.

Heparin-induced thrombocytopenia (HIT) is caused by heparin-dependent, platelet-activating IgG antibodies that increase thrombin generation in vivo, producing a prothrombotic phenotype. In addition to platelet activation, there is in vitro evidence that activation of endothelium and monocytes occurs, perhaps directly by HIT antibodies, but more likely through activated platelet (or microparticle)-endothelial-leukocyte interactions. Patients with cardiac disease receiving heparin present important diagnostic and therapeutic issues when unexpected thrombocytopenia arises. Concomitant vascular disease burden and intravascular catheter use further increase risk of HIT-associated arterial thrombosis in this patient population. Whether arterial thrombosis simply reflects the "hypercoagulability state" of HIT interacting with diseased or injured arteries, or whether arterial "white clots" reflect additional prothrombotic effects of HIT via endothelial and monocyte activation, remains uncertain. Patients with HIT can also develop deep-vein thrombosis, which can progress to limb loss if coumarin (warfarin) leads to severe protein C depletion (coumarin-induced venous limb gangrene). Therapy for patients strongly suspected to have HIT should focus on inhibiting thrombin (or its generation) pharmacologically. Two direct thrombin inhibitors (lepirudin, argatroban) are approved for treating HIT. When using these agents, coumarin anticoagulation should be delayed pending substantial resolution of thrombocytopenia, before cautiously introducing overlapping coumarin therapy.

Monteplase reduces infarct volume and hemorrhagic transformation in rat model of embolic stroke

Monteplase, a modified recombinant tissue plasminogen activator (rt-PA), has a long half-life and reduces binding to plasminogen activator inhibitor. In this study we investigated whether its systemic administration reduces infarct volume without increasing the risk of intra-cerebral hemorrhage. The effect of the drug was tested on an embolic stroke rat model that uses white clots. Thirty minutes after clot embolization, rats were infused with 2.2 mg kg-1 of monteplase or the same amount of saline, over 60 min. Relative regional cerebral blood flow had recovered 60 min after monteplase administration and infarct volume was significantly smaller 24 h after clot embolization in the monteplase-treated rats (47.0 mm3) than in the saline-treated rats (130.4 mm3). Also, the hemorrhagic transformation area was significantly smaller in monteplase-treated rats (0.8 mm2 vs. 18.0 mm2, respectively). These results indicate monteplase can be a promising thrombolytic agent for treatment of the acute stage of cerebral ischemia. [Neurol Res 2002; 24: 311-316]

Multiple Postoperative Thromboembolic Events and Fatal Pulmonary Embolism : the White Clot Syndrome. A Case Report

Multiple Postoperative Thromboembolic Events and Fatal Pulmonary Embolism : the White Clot Syndrome. A Case Report

Medical Management of a Large Aortic Thrombus in a Young Woman With Essential Thrombocythemia

Medical Management of a Large Aortic Thrombus in a Young Woman With Essential Thrombocythemia

Heparin-Induced thrombocytopenia: minimising the risks in the elderly patient.

Heparin therapy may sometimes be seriously complicated by heparin-induced thrombocytopenia (HIT). Heparin use for treatment and prevention of thromboembolism is more common in the elderly and that may be the reason why HIT is reported more frequently in this group of patients. The first approach in the management of HIT is awareness of this disorder. The morbidity and mortality associated with HIT may be reduced by avoiding unnecessary heparin exposure, by reducing the duration of heparinisation and by using low molecular weight heparins rather than unfractionated heparin. A decrease from baseline values of at least 30% in the platelet count, any unexplained thrombotic event and the finding of a white clot at thrombectomy are clinical warning signs that should alert physicians to a possible diagnosis of HIT. Indeed, early clinical recognition of HIT may sometimes prevent the severe complications associated with this disorder. Objective confirmation of the diagnosis of HIT is difficult because none of the available biological tests possess 100% sensitivity or 100% specificity. It is, however, possible to optimise the performances of the functional assay, mainly the platelet aggregation test (PAT), by following the manoeuvres described by differ- ent investigators. The use of 2 classes of assay (functional and antigen assays) and repeat testing on another day can avoid misdiagnosis of HIT. An alternative parenteral anticoagulant treatment is most often mandatory after heparin withdrawal. Danaparoid sodium and lepirudin are 2 drugs that are currently available for the treatment of HIT, and the efficacy of argatroban needs to be confirmed in greater numbers of patients with HIT. The use of these drugs has contributed to the reduction in the mortality and morbidity associated with HIT.

Heparin induced thrombocytopenia and thrombosis

Heparin remains the most commonly used parenteral medication in hospitalized patients. Heparin induced thrombocytopenia (HIT) and heparin induced thrombocytopenia with thrombosis syndrome or the white clot syndrome are important complications of heparin use. This article provides an indepth review of the etiopathogenesis, clinical manifestations, diagnosis, and management options in patients with HIT. Clinical problems associated with HIT such as antiphospholipid antibody syndrome and venous gangrene are described. The management options of HIT patients during cardiac interventional procedures and coronary surgery as well as recent advances in therapeutic options are summarized. Copyright © 2000 by W.B. Saunders CompanyProgress in Cardiovascular Diseases, Vol. 42, No. 4 (January/February), 2000: pp 247-260

Case managing heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) and its two subtypes, early onset (Type I) and delayed onset (Type II), are becoming an increasing concern in acute care. Also called "white clot syndrome," this condition can lead to thrombosis and loss of limb. Alternatives to heparin therapy, such as low molecular weight heparin, are discussed as ways to decrease HIT. An algorithm has been developed to guide identification and monitoring of patients at risk for HIT. The article presents the expanded role of the clinical nurse specialist as case manager in clinically managing patients with actual or potential HIT. The case manager's role for patients receiving heparin lies in increasing the awareness of this condition among all clinicians and serving as a resource for current information regarding its prevention, diagnosis, and treatment.

Etiology of peripheral arterial thromboembolism in young patients

Background: No prior studies have explored the etiology of peripheral arterial thromboembolic events (PATE) in younger patients. Therefore, we analyzed the sources of these events in patients <50 years of age over a recent 10-year period. Diagnostic and work-up strategies will be proposed based on the presence of cardiac or atherosclerotic risk factors. Patients and Methods: The sources of emboli were classified as (1) conventional (cardiac or arterioarterial), (2) unconventional, or (3) unknown. A statistical analysis of risk factors that, if absent, would suggest an unconventional cause was performed. Risk factors included those for cardiac and atherosclerotic disease: coronary artery disease (CAD), valvular disease, smoking, arrhythmia, hypertension, or diabetes mellitus. Results: Overall, 51 patients were identified. Twenty-nine patients (57%) had unconventional causes (8 paradoxical emboli, 4 possible paradoxical emboli, 12 hypercoagulable states, 3 white clot syndromes, and 2 cervical ribs), 17 (33%) had conventional causes, and 5 (10%) were unknown. When the number of cardiac risk factors was ≤1, excluding smoking, the probability of a conventional source was zero, in contrast to 100% if the number of risk factors was >1. When the following risk factors were absent, there were significantly more unconventional than conventional sources of emboli ( P <0.001): smoking (100% versus 0%), CAD (93% versus 7%), arrhythmias (83% versus 17%), hypertension (93% versus 7%), and diabetes mellitus (81% versus 19%). Patients with a conventional source were significantly older (44 versus 38 years). Conclusions: The “unconventional” causes of PATE were responsible for a higher percentage of cases in young patients. An analysis of the number of risk factors was useful in predicting which patients suffered embolic events from conventional sources, with the critical number being >1 (excluding smoking). Therefore, when younger patients present with PATE, and are found to have ≤1 identifiable cardiac risk factor, their work-up should be directed toward the unconventional sources first.

Microcirculatory studies of frostbite injury.

Frostbite represents a spectrum of injury ranging from irreversible cellular destruction to reversible changes seen after rewarming. These changes include increases in tissue edema, circulatory stasis, and progressive thrombosis leading to further tissue necrosis. For this reason, it is often difficult at the time of surgical debridement to determine the extent of frostbite injury. This delayed tissue injury is similar to that seen in muscle during ischemia/reperfusion injury. Muscle that initially appears viable on reperfusion may subsequently necrose due to collapse of the microcirculation. Adherent neutrophils have been specifically cited as important components in ischemia/reperfusion injury and have also been suggested to play a role in frostbite injury. We have used an intravital microscopic muscle preparation to study microcirculatory changes carefully in frostbite injury during rewarming. The right gracilis muscle of male Wistar rats is dissected free from its primary vascular pedicle and the rat is positioned on a specially constructed microsurgical stage. Temperature changes of the muscle are recorded. The prepared axial pattern flap is transilluminated with a microscope and projected on a video screen, allowing measurement of arteriolar diameters and changes in the numbers of stuck and rolling neutrophils before frostbite, during rewarming, and for several hours later. Cold silicone oil is used to freeze the muscle to -5+/-2 degrees C in 2 to 3 minutes and to hold this temperature for 5 minutes. The muscle is rewarmed with 42 degrees C normal saline placed directly on the muscle surface. Baseline vessel diameter and leukocyte counts in 100-mm segments of the microvasculature are recorded as well as at 5, 15, and 30 minutes, and at 1, 2, and 3 hours postrewarming of frozen muscle. Observations from our initial 11 animals show that reperfusion of the muscle following freezing is varied temporally and spatially, with circulation to most vascular segments restored 5 to 10 minutes after rewarming. In 9 of 11 animals we observed the shedding of "white clots" in small arterioles and venules occurring as soon as 5 minutes after thawing. In some instances shedding continued for as long as 1 hour after rewarming. Microvascular hemorrhage was widespread 1 hour following the thaw, but there was no significant increase in neutrophil adherence observed until 3 hours following rewarming. The exact nature of the vascular injury and the composition of the "white clots" are now being determined from ultrastructural studies. Blood flow in microcirculation stops during freezing, but small-vessel perfusion returns immediately on thawing. This suggests that the vascular architecture is maintained during the freezing and thawing. Unlike ischemia/reperfusion injury, neutrophil adhesion plays a smaller role in the early response to frostbite injury. The early microcirculatory observations seen after rewarming suggest progressive and severe perturbations in platelet function and fibrin formation that are significantly different from ischemia/reperfusion injury.

Frontiers in interventional cardiology.

n more than 20 years since the first percutaneous coronary revascularization procedures, the field of interventional cardiology has proliferated beyond all expectations. Now more than 1 million procedures are performed worldwide each year. Stenting has revolutionized the field, which previously relied on balloon dilatation in the majority of patients. With 50% of patients now undergoing stent implantation, the groundwork is laid for further important advances. In this article, we discuss the 4 most important new advances in the field of interventional cardiology: platelet inhibition, prevention of restenosis, stent evolution, and angiogenesis.

Attention shifts to the white clot

Attention shifts to the white clot

EFFECTS OF PLATELETS AND WHITE BLOOD CELLS AND ANTIPLATELET AGENT C7E3 (Reopro TM) ON A NEW TEST OF PAF PROCOAGULANT ACTIVITY OF WHOLE BLOOD.

This study was designed to evaluate the effects of varying concentrations of platelets, white blood cells (WBC) and Fab fragments of a monoclonal antibody (c7E3, Reopro TM) directed at the platelet GpIIb-IIIa receptor complex on ACT-based clot ratio values (hemoSTATUS assay) in healthy volunteers. These measurements were made in heparinized whole blood from 10 normal volunteers in which either platelet or WBC concentrations had been varied by differential centrifugation. In addition, blood collected in either heparin or argatroban was incubated with varying concentrations of c7E3 (Reopro TM). Clot ratio values (%Maximal) in normal blood did not decrease until average platelet counts were less than 50,000. A marked reduction in clot ratios was observed when WBC concentration increased above or decreased below baseline clot ratios within each patient. Strong linear relationships were observed between white cell concentration and clot ratio values when white cell concentrations were either less or greater than baseline values. When argatroban was used as an anticoagulant, inverse relationships were demonstrated between clot ratio values and increasing c7E3 concentration (Ch 3: r=−0.33, Ch4: r=−0.84, Ch5: r=−0.87, Ch 6: r=−0.71). ACT-based clot ratio values determined in heparinized whole blood presumably reflecting PAF inducible platelet procoagulant activity, are affected by platelet concentration when counts are less than 50,000/μ1. The hemoSTATUS test was also found to be by WBC concentration since clot ratio values decreased when WBC counts were below 4,000/μ1 or above 9,000/μ1. A dose-dependent reduction in clot ratio values was also observed with increasing concentrations of c7E3. This test can reliably detect platelet dysfunction only if the platelet count is > 50,000 and the WBC is normal. © 1997 Elsevier Science Ltd

Characterisation of red and white thrombus by intravascular ultrasound using radiofrequency and videodensitometric data-based texture analysis

Visual assessment of intravascular ultrasound (IVUS) video images cannot reliably identify thrombus. We examined if texture analysis of radiofrequency (r.f.) data or videodensitometric data (VD) could distinguish thrombi of different ages and cell compositions. Whole human blood (red clot = RC), platelet-rich plasma (white clot = WC) and plasma ( n = 6/group) were imaged at 4 and 24 h with 30 MHz IVUS transducers. At 4 h, VD- and r.f.-based analyses revealed significant differences between RC and WC with variance (VD red 26.4 ± 2.5, white 33.9 ± 7.8; r.f. red 1.4 ± 0.5, white 4.9 ± 1.3), kurtosis (VD red 0.29 ± 0.9, white 0.23 ± 0.3) and skewness (VD red 0.23 ± 0.13, white 0.35 ± 0.52; r.f. red 0.06 ± 0.01, white −0.06 ± 0.05). Also mean grey-level from both data sets was higher in RC (VD 134.8 ± 18.0; r.f. −13.3 ± 1.2) than in WC (VD 105.3 ± 17.4, r.f. 16.5 ± 2.2) ( p < 0.01). With increasing time, variance increased in WC (5.5 ± 1.5 at 24 h) and decreased in RC (0.9 ± 0.3.3 at 24 h). The more heterogeneous structure of WC may be distinguished from that of RC using texture analysis of either VD or r.f.-signals.

Deep vein thrombosis, pulmonary embolism, and the white clot syndrome

Thromboembolic events such as deep vein thrombosis (DVT) and pulmonary embolism (PE) are very uncommon in the pediatric age group; even more rare is the white clot syndrome. We present the case of a 13-year-old girl who presented with no known risk factors for thromboembolic disease or cardiopulmonary complaints, yet was found to have extensive lower extremity DVT and PE. This patient also suffered the rare but potentially devastating complication of heparin therapy referred to as the white clot syndrome, resulting in amputation of the lower extremity. Greater awareness of both thromboembolic disease in children and the white clot syndrome may lessen the morbidity and mortality associated with these entities.

Effect of Early Treatment with Tirilazad (U74006F) Combined with Delayed Thrombolytic Therapy in Rat Embolic Stroke

Sixty-eight rats were embolized in the right carotid territory with a 200-µl suspension of white clots made from autologous blood. The purpose was to investigate the effect of early treatment wit

Two unusual case presentations of the white clot syndrome and their rehabilitation: F. Marlene Perez, MD (The New York Hospital-Cornell Medical Center, New York, NY); Elisabeth A. Lachmann, MD

Two unusual case presentations of the white clot syndrome and their rehabilitation: F. Marlene Perez, MD (The New York Hospital-Cornell Medical Center, New York, NY); Elisabeth A. Lachmann, MD

Fatal Thrombocytopenic Coagulopathy After Cardiopulmonary Bypass: Clinicopathologic Correlations Implicating Heparin

Heparin-associated thrombotic thrombocytopenia after cardiopulmonary bypass is frequently lethal. The propensity for this syndrome generally goes unrecognized because thrombocytopenia is common in the early postoperative period and because testing for heparin-induced platelet antibody may not distinguish between patients with thrombocytopenia alone and those in whom associated thrombi (the white clot syndrome) may develop. Moreover, differentiation between heparin-associated thrombotic thrombocytopenia and a consumptive coagulopathy may be difficult, and intervention may be inappropriate because of diametrically opposite treatments. Our experience with three cases and the necropsy findings in two of them demonstrate that postbypass thrombocytopenic coagulopathy may be a clinical and pathologic spectrum of consumptive coagulopathy, with heparin as the major premorbid factor. This report further emphasizes the need for vigilance in assessing certain patients preoperatively to lessen the high risk of morbidity and mortality associated with this syndrome.

Optimal outcome for “high-risk” carotid endarterectomy

While carotid endarterectomy (CEA) can often be accomplished with a very low stroke risk, certain scenarios—prior ipsilateral stroke, contralateral carotid occlusion, or acute cerebral ischemia—have been associated with neurologic morbidity and mortality rates exceeding 10%. The routine use of temporary intraluminal carotid shunts has been thought to be obligatory in such patients, notwithstanding the fact that these devices are obtrusive and may be associated with an increased risk of perioperative stroke. Among 175 patients undergoing CEA, 68 could be classified as “high-risk” (contralateral carotid occlusion, n = 24; prior ipsilateral stroke, n = 28; acute cerebral ischemia, n = 16). CEA was performed under regional or local anesthetic block in all 68 patients. Sixty-six patients (97%), including 22 of 24 (92%) with contralateral carotid occlusion, underwent CEA (carotid occlusion times averaging 22 minutes [range: 12 to 42 minutes]) without insertion of a carotid shunt. Two patients (2.9%) with contralateral carotid occlusion lost consciousness 7 and 10 minutes after carotid clamping, but regained neurologic normalcy after shunt insertion. A single patient (1.5%) experienced a fatal stroke due to heparin-induced “white clot” syndrome. Rates of shunt insertion and of perioperative stroke did not differ from those in 107 “low-risk” CEA patients. Cerebral collateral circulation is well developed even in compromised CEA patients. The necessity for temporary carotid shunts may be reduced by the use of “awake” anesthesia in such cases. Carotid shunting may be no more necessary, and operative outcome no less favorable, in “high-risk” than in uncomplicated CEA patients.

Current trends in the development of anticoagulant and antithrombotic drugs

Developments in biotechnology, synthetic chemistry, and extraction methods have contributed significantly to provide many newer antithrombotic and anticoagulant drugs. Many of these drugs exhibit mechanisms of actions distinct from heparin and oral anticoagulants. The depolymerization of heparin has resulted in the development of LMWHs. These drugs have now attained the agent of choice status for the prophylaxis of postsurgical and medical thrombotic disorders. LMWHs are now being clinically evaluated for the treatment of established thrombosis and prevention of post-acute angioplasty occlusion and reocclusion. Many newer applications of these agents will be proposed in coming years. Synthetic and recombinant antithrombin agents, such as hirudin and hirulog, have been claimed to exhibit effective anticoagulant and antithrombotic actions. The clinical data, however, are rather limited, and additional validation studies are needed. These agents, however, provide an alternate anticoagulation approach in patients who are refractory to the actions of heparin or who developed heparin-induced thrombocytopenia. Both hirudin and peptide conjugates are undergoing extensive clinical trials throughout the world in various indications. Once validated, their optimized use will provide physicians and surgeons an alternate anticoagulant approach for heparin-compromised patients. Glycosaminoglycans, such as dermatan sulfate, heparan sulfate, and other mixtures, have been developed for various indications. These drugs, however, are relatively inferior to LMWHs for the prophylaxis of thromboembolism. Although these agents have been used for phlebitis and other indications, well-designed objective clinical trials are not available at this time. Because these agents exhibit other effects, such as the effect on smooth muscle cell proliferation, these may be of some value in the control of post-percutaneous transluminal coronary angioplasty restenosis. Several synthetic analogs of heparin and related glycosaminoglycans have also been developed. One of these agents is a synthetic pentasaccharide that represents the AT-III binding site in the heparin molecule. This agent produces a strong anti-Xa effect and is devoid of any antithrombin actions. This agent is currently being developed for the prophylaxis of thromboembolism. The synthetic pentasaccharide is devoid of any effects on platelets and thus does not produce any thrombocytopenic effects. Thus it may be useful in those patients who develop thrombocytopenia and white clot syndrome. A hypersulfated lactobionic acid analog has also been developed as an antithrombotic agent. This agent was initially found to produce its antithrombotic action via HC-II. More recent data, however, show that it also releases TFPI from endogenous sites.(ABSTRACT TRUNCATED AT 400 WORDS)

White clot syndrome associated with renal failure.

In a minority of patients, heparin administration is associated with thrombocytopenia and this thrombocytopenia may be associated with thromboembolic events. Heparin-associated thromboembolism is described as heparin-associated thrombocytopenia and thrombosis or white clot syndrome. White clot syndrome is caused by antibodies to a heparin-platelet membrane complex. The diagnosis carries a high mortality and morbidity from limb thromboembolism. Treatment includes discontinuation of heparin, use of alternate anticoagulants, and aggressive treatment of thromboses. A case in which acute renal failure occurred in the setting of heparin treatment and thrombocytopenia is described, and evidence that renal failure was a result of white clot syndrome is provided.