Heparin-induced thrombocytopenia occurring after surgical treatment of atrial myxoma: A case report

Introduction Heparin-induced thrombocytopenia (HIT) is an acquired, prothrombotic disorder, caused by antibodies to a complex of heparin and platelet factor 4 (PF4) that activates platelets, resulting in the release of procoagulant microparticles, thrombocytopenia occurrence, generation of thrombin, and frequent thromboses. Case Outline We present a case of severe HIT in a 68-year-old female, which occurred after cardiosurgery of the left atrial myxoma with the aim to point out the importance of differential diagnosis of thrombocytopenia in patients recently exposed to heparin. Platelet count dropped on the eleventh postoperative day, six days after unfractioned heparin and enoxaparine treatment, to 4?109/l. The correct diagnosis failed to be made at first. Since thrombocytopenia remained refractory to a corticosteroid treatment and platelet transfusion, the patient was hospitalized on the 13th postoperative day at the Institute of Hematology. The diagnosis of HIT was confirmed with the high-probability clinical score (4T's) and strongly positive antiheparin-PF4 (PaGIA) test as well as positive platelet aggregation test. The treatment started with a smaller therapeutic doses of danaparoid than recommended of 750 U intravenous bolus and was followed by continuous infusions of 100 U per 1 h and intravenous gammaglobulins in full dosage for four days. The platelet count started to rise on the third day and it was completely normalized on the 5th day of the therapy. Conclusion Treatment of severe HIT with small doses of danaparoid supplemented by intravenous gamma globulin was successful. Additional awareness of heparin-induced thrombocytopenia is needed, especially of HIT in differential diagnosis of thrombocytopenia in patients recently exposed to heparin.

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Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation

Hematology ◽

10.1182/asheducation-2009.1.225 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 225-232 ◽

Cited By ~ 14

Author(s):

Thomas L. Ortel

Keyword(s):

Platelet Count ◽

Heparin Therapy ◽

Severe Thrombocytopenia ◽

Drug Induced ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Immune Mediated ◽

Number Of Patients ◽

Increased Risk ◽

Antibody Levels

Abstract Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of ~50 to 60 × 109 platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

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The Incidence of Thrombosis in Patients with Isolated Heparin Induced Thrombocytopenia.

Blood ◽

10.1182/blood.v108.11.1049.1049 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1049-1049 ◽

Cited By ~ 1

Author(s):

Rachel P. Rosovsky ◽

Omar I. Abdel-Wahad ◽

Elizabeth M. Van Cott ◽

David J. Kuter

Keyword(s):

Platelet Count ◽

Mortality Rate ◽

Massachusetts General Hospital ◽

Thrombotic Event ◽

Radiographic Examination ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Total Incidence ◽

Objective Evidence ◽

Heparin Exposure

Abstract Introduction: Heparin-induced thrombocytopenia type-II (HIT) is a serious prothrombotic disorder caused by heparin exposure. The incidence of thrombosis in patients with isolated HIT, defined as HIT without clinically evident thrombosis at the time of diagnosis, is not well established. Aim: The purpose of this prospective study was to determine the total incidence of thrombotic events after diagnosis of isolated HIT from radiographic evidence of asymptomatic deep venous thrombosis (DVT) plus radiographic confirmation of symptomatic thrombosis. Patients and Methods: We evaluated all patients with a positive enzyme-linked immunoassay (ELISA) for heparin-platelet factor 4 (PF4) antibody (Ab) daily at Massachusetts General Hospital from 10/10/05 to 5/13/06. Inpatients with (1) a positive PF4 Ab test, (2) thrombocytopenia, as defined by a ≥50% drop from baseline platelet count and/or a fall in platelet count to <150×109/L, in association with heparin exposure, (3) no signs or symptoms of thrombosis at time of the positive Ab test, and (4) no other definitive etiology of thrombocytopenia were considered to have isolated HIT and included for study. Patients with a prior diagnosis of HIT, DVT, pulmonary embolism, or peripheral arterial thrombosis were excluded. Within 72 hours of diagnosis and of initiation of a non-heparin anticoagulant, all included patients underwent radiographic examination for asymptomatic DVT in the lower extremities (LE). Objective evidence of thrombotic events other than LE DVT after the diagnosis was also recorded. Daily platelet count, type and timing of all anticoagulants, use of blood products, and PF4 Ab titer were collected to determine if there was an association between these factors and development of thrombosis. Mortality rate during hospitalization was also recorded. Results: Of the 158 patients with a positive heparin-PF4 Ab, 64 patients met criteria for study, 14 of which were lost to follow-up. Among the 50 remaining eligible patients, the total incidence of thrombosis was 20% (12% were found to have an asymptomatic thrombotic event and 8% developed a symptomatic thrombotic event). Development of thrombosis was independently associated with platelet transfusion (p=0.005) and with the degree of platelet count nadir as expressed by platelet count (p=0.038) or by percent decrease from baseline (p=0.031). There was no association between the PF4 Ab titer or the type and timing of non-heparin anticoagulant and development of thrombosis. The overall mortality rate in patients diagnosed with isolated HIT during hospitalization was 22%. Conclusion: The total incidence of thrombotic events in isolated HIT was 20%, with greater than half of the events being asymptomatic thromboses found only by radiographic examination. This high incidence of asymptomatic LE DVT suggests that routine investigation for LE DVT should be performed in this patient population and that patients with isolated HIT should be treated with a non-heparin anticoagulant. Our findings also confirm the current recommendation to avoid platelet transfusions in patients with isolated HIT as we found an increased rate of thrombosis associated with this practice.

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Spontaneous Heparin-Induced Thrombocytopenia and COVID-19 Infection

Blood ◽

10.1182/blood-2021-151590 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4216-4216

Author(s):

Suneetha Amara

Keyword(s):

Platelet Count ◽

Conflicts Of Interest ◽

Hospitalized Patients ◽

Target Range ◽

Low Grade ◽

Primary Therapy ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

The Right ◽

D Dimer

Abstract Background and Objective: Heparin-induced thrombocytopenia (HIT) can develop if immune responses to infections become pathologic in the presence of heparins. Low molecular weight heparin or unfractionated heparin are recommended for prophylaxis and treatment of venous thromboembolic disease in hospitalized patients with Covid-19 infection but may trigger HIT. Our aim is to alert clinicians that HIT occurs in association with Covid-19 infections even in the absence of prior exposure and may not be easily recognized without a high index of suspicion. Case Summary: A 33-year-old previously healthy male was initially evaluated for low grade fever, dyspnea without hypoxia and cough. A Covid-19 PCR swab was negative despite a recent exposure. He was treated with azithromycin. However, his symptoms did not improve, he then developed right leg swelling and hypoxia, so he was re-evaluated. CTA of the chest showed bilateral pulmonary emboli and ground-glass opacities at the lung bases. Venous Duplex Ultrasound showed non-occlusive thrombus in the deep veins of right lower extremity. He was hospitalized and placed on oxygen and heparin. Covid-19 swab was negative again. Laboratory tests before heparin showed a decreased platelet count of 64,000 k/ul, elevated prothrombin time of 16.4 seconds, normal aPTT at 30.8 seconds, decreased serum fibrinogen at 120 mg/dl and markedly elevated D-dimer at 59,966 ng/ml. Lupus anticoagulant and anti-phospholipid antibody tests were negative. On heparin at the desired therapeutic aPTT target range, the right leg became significantly swollen and painful by day five. Platelet count had decreased further to 39,000 k/ul. Repeat doppler examination of the right leg now showed more severe and extensive deep venous thrombosis. D-dimer had increased to 125,133 ng/ml. The HIT 4T score was 4, suggesting intermediate probability. Rapid HIT immunoassays on 2 separate samples were positive. Heparin was discontinued and he was placed on argatroban. Serotonin release assays on 2 separate samples came back positive. Suspicion for Covid-19 infection remained high and so a Covid-19 serology sample was obtained which was positive for IgG. A repeat nasopharyngeal swab at this time turned positive. He did not receive any COVID specific treatments. As viability of his leg appeared threatened, he underwent right iliofemoral vein thrombectomy with arteriovenous fistula creation. He improved on argatroban and was transitioned to apixaban with gradual normalization of hemostasis laboratory parameters, improvement in hypoxemia and fading clinical symptoms, he was discharged home on day 15. Conclusion: Current consensus guidelines for thromboprophylaxis and treatment of thromboembolism in hospitalized patients with Covid-19 infection recommend heparins as primary therapy to reduce morbidity and mortality. However, our report in addition to the two previous reports of HIT in Covid-19 patients illustrate that HIT can be a complication in the setting of Covid-19 infection. Further, our report also highlights that HIT with thrombosis can occur in a spontaneous manner in the absence of prior heparin exposure, which has been so far studied only in bacterial infection with the hypothesis that Platelet factor 4 (PF4) can bind to negatively charged polysaccharides on the surface of bacteria, triggering an immune response. Disclosures No relevant conflicts of interest to declare.

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Left atrial myxoma in syncope differential diagnosis: different perspectives

BMJ Case Reports ◽

10.1136/bcr-2021-243529 ◽

2021 ◽

Vol 14 (8) ◽

pp. e243529

Author(s):

Hugo Almeida ◽

João Rodrigues ◽

Beatriz Rodríguez-Alonso ◽

Rita Fernandes

Keyword(s):

Differential Diagnosis ◽

Left Atrial ◽

Atrial Myxoma ◽

Left Atrial Myxoma

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EFFECT OF A SYNTHETIC ANTICOAGULANT (MD 805) ON PLATELETS IN HUMAN VOLUNTEERS AND HEMODIALYSIS PATIENTS.

10.1055/s-0038-1643457 ◽

1987 ◽

Author(s):

T Matsuo ◽

T Yamada ◽

K Nakao

Keyword(s):

Platelet Count ◽

Thrombus Formation ◽

Normal Subjects ◽

Hemodialysis Patients ◽

Normal Range ◽

Synthetic Compound ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Human Volunteers ◽

Platelet Release

Twelve normal subjects were injected with 5000 U of commercial mucous heparin with or without preloading of 1.0 g aspirin, and 0.2 mg/kg MD 805, an arginine derivative, which is a new synthetic compound with an extremely strong affinity for thrombin, at an interval of 4 weeks after each injection. Heparin injection with or without aspirin significantly increased platelet factor 4 release. In contrast, the preloading of aspirin significantly inhibited the decrease of platelet count and the elevation of /8 thromboglobulin induced by heparin. However, MD 805 had no effect on platelet release proteins, and adequate anticoagulation by APTT was still present 60 min after the injection. MD 805 shows no stimulative effects on platelets such as with heparin.In the case of the patient's study, three patients complicated with heparin induced thrombocytopenia plus thrombus formation in the extracorporeal circulation during hemodialysis, and were treated with MD 805 instead of heparin. The platelet counts in those patients quickly returned to within the normal range, and adequate anticoagulation was obtained in the following hemodialysis sessions and no further bleeding or clot formation was noted.In conclusion, MD 805 may represent a useful alternative anticoagulant in patients with heparin induced thrombocytopenia.

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A “Catastrophic” Heparin-Induced Thrombocytopenia

Case Reports in Medicine ◽

10.1155/2020/6985020 ◽

2020 ◽

Vol 2020 ◽

pp. 1-3 ◽

Cited By ~ 3

Author(s):

D. Barcellona ◽

M. Melis ◽

G. Floris ◽

A. Mameli ◽

A. Muroni ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Bleeding Complications ◽

Catastrophic Antiphospholipid Syndrome ◽

Platelet Factor ◽

Cerebral Vessel ◽

Heparin Induced Thrombocytopenia ◽

Unfractioned Heparin ◽

Platelet Protein ◽

Pathological Conditions ◽

Life Threatening

Background. Heparin-induced thrombocytopenia (HIT) is a transient, antibody-mediated thrombocytopenia syndrome that usually follows exposure to unfractioned heparin (UFH) or low-molecular-weight heparin (LMWH). In contrast to other pathological conditions which lead to thrombocytopenia and bleeding complications, HIT results in a paradoxical prothrombotic state. It is caused by antibodies directed to complexes containing UFH or LMWH and a self-platelet protein: the platelet factor 4 (PF4). The heparin-PF4 immune complex leads to activation of platelets, monocytes, and endothelial cells which release procoagulant proteins and tissue factor with subsequent blood coagulation activation. Case Report. We describe the case of a woman undergone to knee replacement and affected by urosepsis who developed a HIT after exposure to enoxaparin. The thrombotic burden was very impressive involving the arterial and venous cerebral vessel and the venous pulmonary, hepatic, and inferior legs vascular beds. The patient was successfully treated with fondaparinux without recurrent thrombosis or bleeding. The clinical scenario could be named “catastrophic HIT” like the catastrophic antiphospholipid syndrome since they have a similar pathogenetic mechanism involving both platelets and monocytes procoagulant activities and a similar clinical manifestation with a life-threatening multiple arterial and/or venous thromboses. Conclusion. Patients presenting with HIT could show a very impressive thrombotic burden resembling to that of the catastrophic antiphospholipid syndrome. A careful differential diagnosis should be made towards other pathological conditions which lead to thrombocytopenia to avoid an unnecessary and potentially harmful platelet transfusion. Although fondaparinux is off-label, its use in patients with HIT is simple and seems to be effective.

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Pattern of Platelet Recovery in Predicting Outcome in Heparin-Induced Thrombocytopenia and Thrombosis.

Blood ◽

10.1182/blood.v108.11.4085.4085 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4085-4085

Author(s):

Indu Sabnani ◽

Ajaz Khan ◽

Patricia Tsang

Keyword(s):

Platelet Count ◽

Early Diagnosis ◽

Liver Dysfunction ◽

Patient Management ◽

Response To Therapy ◽

Cardiac Diseases ◽

Platelet Factor ◽

Platelet Recovery ◽

Heparin Induced Thrombocytopenia ◽

Recovery Group

Abstract Heparin-induced thrombocytopenia and thrombosis (HITT), a severe immune-mediated drug reaction, is often underdiagnosed. Early management of HITT with alternative anticoagulants can result in a favorable outcome. However, the morbidity and mortality associated with HITT remain high, posing challenges for patient management. We describe the clinical profile and pattern of platelet count recovery in a cohort of 34 patients diagnosed with HITT. This retrospective study consists of 164 patients screened for HITT over 18 months at our institution based on positive platelet factor 4 (PF4) IgG antibodies in the proper clinical setting. Patients who tested positive were divided on the basis of recovery of platelet count (increase to >100 × 109/L or by 1.5-fold by day 5 of diagnosis) into two groups: delayed and normal recovery. Of the 164 patients screened, 107 were admitted with cardiac diseases while 57 non-cardiac conditions. A total of 34 patients (21%) were tested positive for PF4 antibodies. Patients with underlying cardiac conditions were more likely to be diagnosed with HITT than non-cardiac patients (28% versus 7%, p=0.0012). The male to female ratio was 1:1.1, and the median age was 65 years. Nineteen of 34 patients (56%) had delayed platelet recovery, while the remaining 15 patients (44%) had normal platelet recovery by day 5. The mortality rate was 68% (13 of 19) in the delayed recovery group, compared to only 7% (1 of 15) in the normal recovery group (p=0.0004). Twelve of the 34 patients with liver dysfunction had delayed platelet recovery and died (figure 1). There were 6 venous and 5 arterial thrombotic episodes. A total of 13 patients (38%) were treated with Argatroban, a direct thrombin inhibitor (DTI) indicated for the treatment of HITT, but it did not seem to improve platelet recovery (Table 1). Eight of the 13 treated patients (62%) and 11 of the 21 untreated patients (52%) showed no platelet recovery by day 5. In conclusion, early diagnosis of HITT is critically important for patient management, and yet, diagnosis is often elusive due to a general lack of awareness of this condition. Underlying cardiac diseases appear to predispose patients to HITT, probably due to previous exposure and sensitization to heparin. Despite the availability of new anticoagulants, HITT remains an undertreated and highly fatal condition with overall mortality of 38% in our series. Underlying liver dysfunction appears to be associated with delayed platelet recovery and poor survival. Affect of DTI on platelet recovery needs to be further investigated. Optimal response to therapy requires early diagnosis and intervention. Further studies are necessary to enhance our understanding of this devastating condition to facilitate early diagnosis and proper treatment. Treatment and Survival of HITT Patients Outcome Treated with DTI Not treated Total Dead 6 7 13 Alive 7 14 21 Total 13 21 34 Pattern of Platelet Recovery in Patients with HITT with Delyaed Recovery > 5 days Pattern of Platelet Recovery in Patients with HITT with Delyaed Recovery > 5 days Pattern of Platelet Recovery in Patients with HITT with Delyaed Recovery < 5 days Pattern of Platelet Recovery in Patients with HITT with Delyaed Recovery < 5 days

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Spontaneous Heparin-Induced Thrombocytopenia Syndrome: Two New Cases and a Proposal For Defining This Disorder

Blood ◽

10.1182/blood.v122.21.2328.2328 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2328-2328 ◽

Cited By ~ 1

Author(s):

Theodore E. Warkentin ◽

Paul Andrew Basciano ◽

Richard A. Bernstein

Keyword(s):

Platelet Count ◽

Platelet Activation ◽

Research Funding ◽

Left Vertebral Artery ◽

Platelet Factor ◽

Shoulder Hemiarthroplasty ◽

Heparin Induced Thrombocytopenia ◽

Activation Assay ◽

Count Recovery ◽

Heparin Exposure

Abstract Introduction Heparin-induced thrombocytopenia (HIT) is a transient, autoimmune-like, prothrombotic disorder caused by heparin-dependent, platelet-activating IgG reactive against platelet factor 4/heparin (PF4/H). There is an emerging literature (Am J Med 2008;121:632-6. J Thromb Haemost 2008;6:1598-1600; Thromb Haemost 2013;109:669-75) pointing to rare instances of “spontaneous” HIT in patients without preceding heparin. We report 2 new cases and propose a definition for this controversial disorder. CASE #1. A 62-y.o. man presented with left middle cerebral artery stroke and thrombocytopenia (platelet count, 65×109/L). There was no previous history of thrombocytopenia, surgery, hospitalization, or heparin exposure. Clot extraction performed with heparin was complicated by further platelet count decline to 27 (nadir) and progressive thrombosis of the carotid artery. Aspirin was started, and the platelets recovered to >150 by day 13. CASE #2. A 54-y.o. female developed right leg swelling, left-upper extremity weakness/paresthesias, and thrombocytopenia (61×109/L) 15 days post-shoulder hemiarthroplasty; no intra-/postoperative heparin had been given. Brain MRI demonstrated acute infarct in the left posterior inferior cerebellar artery territory; angiography showed non-visualization of the left vertebral artery. Ultrasound revealed right lower-limb deep-vein thrombosis. Heparin treatment resulted in further platelet count fall to 37 (nadir). Treatment with argatroban, followed by fondaparinux, was associated with platelet count recovery to >150 by day 39. Methods Testing for HIT antibodies was performed by commercial EIA-IgG/A/M (Immucor GTI Diagnostics), in-house EIA-IgG (McMaster), and serotonin-release assay (SRA). Results Both patients’ sera (obtained before any heparin administration) tested strongly positive for HIT antibodies (Table), including strong platelet activation at 0.1 and 0.3 IU/mL heparin, as well as at 0 U/mL heparin, with no platelet activation at 100 IU/mL heparin: these serological features are characteristic of “delayed-onset HIT” (Ann Intern Med 2001;135:502-6). Antibody reactivity declined markedly by 2 to 4 weeks (including loss of platelet-activating properties at 0 IU/mL heparin), in keeping with the usual transience of HIT antibodies (N Engl J Med 2001;344:1286-92), and paralleling both patients’ platelet count recovery. Discussion These cases further support spontaneous HIT as an unusual explanation for acute arterial stroke and thrombocytopenia. One patient had preceding orthopedic surgery, an event previously reported with spontaneous HIT (Thromb Haemost 2013;109:669-75). The strong serum-dependent platelet activation at 0 IU/mL heparin helps to explain how thrombocytopenia and thrombosis can occur in a patient not receiving heparin. RECOMMENDATION. Based on the serological findings of these and previous cases, we propose that a definitive diagnosis of spontaneous HIT syndrome should be based upon all of the following criteria: thrombocytopenia, thrombosis, lack of proximate heparin exposure, strong-positive PF4-dependent immunoassay(s), and a strong-positive platelet activation assay featuring both heparin-dependent (e.g., high heparin neutralization) and heparin-independent platelet activation (at 0 IU/mL heparin). Disclosures: Warkentin: Pfizer Canada: Honoraria; Paringenix: Consultancy; Immucor GTI Diagnostics: Research Funding; WL Gore: Consultancy; GSK: Research Funding.

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Heparin-induced thrombocytopenia

Hematology ◽

10.1182/asheducation-2013.1.668 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 668-674 ◽

Cited By ~ 38

Author(s):

Grace M. Lee ◽

Gowthami M. Arepally

Keyword(s):

Differential Diagnosis ◽

Heparin Therapy ◽

Hospitalized Patients ◽

Diagnostic Approach ◽

Laboratory Evaluation ◽

Common Occurrence ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Critical Elements ◽

The Common

Abstract Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies that recognize complexes of platelet factor 4 (PF4) and heparin. HIT is frequently considered in the differential diagnosis of thrombocytopenia occurring in patients on heparin therapy. HIT is a challenging diagnosis because of routine heparin use in hospitalized patients, the common occurrence of thrombocytopenia, and high rates of anti-PF4/heparin seroconversions in patients treated with heparin. Our diagnostic approach to HIT is presented here, underscoring critical elements of clinical and laboratory evaluation.

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Heparin-Induced Thrombocytopenia: Prevalence in a Large Cohort of Patients and Confirmed Role of PF4/Heparin Complex as the Main Antigen for Antibodies

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602969700300309 ◽

1997 ◽

Vol 3 (3) ◽

pp. 203-209 ◽

Cited By ~ 3

Author(s):

Fabrizio Fabris ◽

Immacolata Cordiano ◽

Federica Salvan ◽

Leopoldo Saggin ◽

Giuseppe Cella ◽

...

Keyword(s):

Molecular Weight ◽

Platelet Count ◽

Platelet Factor 4 ◽

Enzyme Linked Immunosorbent Assay ◽

Low Molecular Weight ◽

Dependent Manner ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Heparin Treatment ◽

Daily Dose

We performed a retrospective study on the prevalence of heparin-induced thrombocytopenia (HIT) in 233 patients receiving hog mucosa heparin therapy. Of these, 82 patients received s.c. calcium heparin, 130 patient received unfractionated (UF) i.v. heparin, and 21 patients received low molecular weight heparins (LMWH). An additional four patients, referred to our consultation and diagnosed by us as having clinically active type II HIT (HIT-II) were also studied. The mean platelet count of the 233 patients receiving heparin showed a significant decrease after 2 days of heparin treatment and a following significant increase 6 days later (basal: 257 ± 147 x 109 platelets/L; day 2: 239 ± 122, p < 0.0002; day 6: 286 ± 119, p < 0.004). Of the 212 patients receiving UF heparin, 13 (6%) fulfilled the criteria for HIT-II: seven of these had received i.v. heparin (mean daily dose 26,600 ± 4,082 IU ± SD) and six had received s.c. heparin (mean daily dose 21,428:t 6,900 IU). Their mean basal platelet count was 226 ± 100 SD × 109 platelets/L and the nadir during heparin treatment was 78 ± 39 x 10 9 platelets/L. Thrombotic complications occurred in four (30.7%) of the 13 patients with HIT-II. Since the immunological mechanism has been demonstrated for HIT-II and since platelet factor 4 (PF4) was identified as the co-factor for the binding of heparin-related antibodies, we set up our own enzyme-linked immunosorbent assay (ELISA) for testing antibodies against PF4/heparin complex bound through electrostatic bridges to the solid phase. The highest binding capacity of HIT-related IgG to the multimolecular complex was obtained at 20 μg/ml for PF4 and 3 μg/ml for heparin, corresponding to 250 ng of PF4 and 42 ng of heparin in each microtiter well. Such binding was inhibited in a dose-dependent manner by increasing amounts of heparin, protamine hydrochloride, and a monoclonal antibody anti-human PF4 clone 1OB2. We observed that HIT-related antibodies bound also to PF4/LMWH complexes but the optimal PF4/glycosaminoglycan ratio appeared more critical for LMWH (enoxaparin, fraxiparin, and pamaparin) than for UF heparin. Sera from eight patients with HIT-II were tested by PF4/heparin ELISA; six of these had IgG against the complex PF4/heparin and three also had IgM. The persistence of HIT-related antibodies was investigated in three patients: in one such antibodies were still detectable 3 years after the acute episode, while in the other two, they disappeared after 6 months and 1 year, respectively. Key Words: Heparin-related anti body—Platelet factor 4 (PF4)—Heparin—Low molecular weight heparin—Thrombocytopenia—Thrombosis.

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