review article heparin induced thrombocytopenia · review article heparin induced thrombocytopenia...

Eur J Vasc Endovasc Surg 11, 260-269 (1996)

REVIEW ARTICLE

Heparin Induced Thrombocytopenia

Maciej DryjskP* and Hanna Dryjski 2

1Departments of Surgery, Division of Vascular Surgery, State University of New York, Buffalo, U.S.A. and 2Department of Dental Biomaterials Science, Karolinska Institute, Stockholm, Sweden

Introduction

Heparin is a negatively charged non-branching muco- polysaccharide of glycosaminoglycan type. Commer- cially available preparations are obtained from porcine intestinal mucosa or bovine lung. These preparations are heterogeneous and contain contaminating sub- stances. The molecular weight of heparin chains vary from 3000 to 60 000 Daltons, but in commercial preparations are usually 15 000 to 20 000 DaltonsJ "2 The low molecular weight (LMW) heparins have an average molecular weight of 3000 to 10 000 Daltons. Semisynthetic heparinoid, Org 10172 (Orgaran, Lomo- paran) contains only 3% LMW heparin with the remaining bulk of this material consisting of other glycosaminoglycans. 3

The anticoagulant effect of heparin is dependent on its ability to reversibly bind antithrombin III and to catalyse its inactivation of thrombin, factor Xa, IXa, XIa, XIIa and prekallikrein. Elimination kinetics are principally mediated by a non saturable mechanisms. Heparin is metabolised in the liver but elimination half-life is increased in patients with kidney disease, suggestin§ a significant renal component to clearance.

The ability of heparin to induce thrombocytopenia (heparin induced thrombocytopenia, HIT) after an intravenous injection was recognised in animals in 19394 and in man in 1948. 5 Thromboembolic complication resulting from heparin treatment was first re~orted in 1958 by Weismann and Tobin. 6 Roberts et al / described several cases of peripheral arterial

*Please address all correspondence to: Maciej Dryjski, Department of Surger36 State University of New York, Buffalo, Millard Fillmore Hospital 3 Gates Circle, Buffalo, New York 14209, U.S.A.

Based on the clinical features and pathophysiological mechanisms two types of heparin induced thrombocytopenia (HIT) have been ident.ified. 9-15 Type I HIT is non-immune (non-idiosyncratic) and is caused by the ability of heparin to increase the platelets response to aggregating stimuli. It has a rapid onset, usually within 1-5 days after the initiation of heparin therapy. Although, platelet counts may fall significantly they usually remain between 100 000 to 150 000/mm 3 and typically return to normal values within i to 5 days in spite of continued heparin therapy, n'16-~s The incidence of this mild form of HIT is about 10-20%. 19'2° Thus, this type of HIT is probably quite common, but it is not associated with any detrimental effects and therefore rarely noted clinically. ~5

Type II HIT (idiosyncratic) is more serious and is frequently associated with limb and life threatening complications. 18'21-23 The incidence of type II HIT is subject to debate with estimates ranging from negli- gible to 30% 9"21'23-26 Approximately 107o of patients with type II HIT will develop thromboembolic complications (TEC). 12'27-32 Some authors estimate that the risk of TEC in patients who become thrombocytopenic

emboli occurring in patients being treated with heparin and suggested that it might be caused by an immunologically mediated platelet aggregation. Rhodes et al. 8 found heparin dependent complement fixing activity in the gamma G globulin fraction of serum in several patients. Subsequently, the patho- physiologic mechanisms and the clinical features of HIT and thrombosis have been defined more dearly.

Clinical Features and Incidence

1078-5884/.96/030260 + 10 $12.00/0 © 1996 W. B. Saunders Company Ltd.

Heparin Induced Thrombocytopenia 261

may be as high as 20% 9 or even higher. 33 Based on the review of 22 prospective studies Schmitt and Adelman estimated the incidence of HIT with TEC to be less than 1%, 24 yet, they pointed out that there were no adequately designed studies to estimate the true incidence of HIT-related thrombosis or haemorrhage.

In the reported cases, more than 90% of patients with severe HIT (platelet counts < 50 000 mm 3) and about 95% of patients with HIT and TEC developed the syndrome after 6 days or more after initiation of heparin treatment. 34 However, if the patient has been previously exposed to heparin, thrombocytopenia may occur within hours or days following re-exposure. 9'21'35 HIT occur in all age groups including young children and the newborn. 36'37

Type II HIT is characterised by marked thrombocytopenia with platelet counts often < 50 000 mm 3. Platelet counts usually recover within 5 to 6 days after cessation of heparin treatment, but sometimes the recovery may be delayed for up to 6 weeks. 38 TEC are always accompanied by a fall in platelet counts, but thrombocytopenic levels are not always reached. 33'39"4° In general, the lower the platelet count, the higher the risk of TEC. 41 The platelet counts in HIT cases with TEC is usually 40-60 000/mm 3, but platelets counts as low as 5000/mm 3 have been reported. 9'27"42 Global activation of the coagulation cascade may occur during an acute thrombogenic episode. 43 One of the first symptoms of impending TEC can be unexplained abdominal or lumbar pain, 42'44 and/or the development of heparin resistance. 8'21'35 Inability to maintain an adequate level of anticoagulation despite increased doses of heparin may be caused by release of platelet factor 4, which is heparin neutralising factory "35'46-~8 Heparin induced skin necrosis may also precede the development of HIT with TEC. 47-5°

A wide clinical spectrum of thrombotic complications has been described in HIT. The most common events include lower limb arterial thrombosis, 6"7'21'22"26'35'45 myocardial infarction, 1°'35'45 thrombotic cerebrovascular accidents. 22'33'35'49 Less frequently

49 50 reported complications includes skin necrosis, " upper limb arterial occlusions, 51 renal artery and vein thrombosis, 6'52'53 mesenteric ischaemia, 2L22'39 spinal artery thrombosis, 13 arterial graft thrombosis, 21'54 spleen infarction, 22 adrenal thrombosis and/or haemorrhage resulting in acute or chronic adrenal insuffi- ciency, 55"56 and aorta thrombosis with multiorgan failure. 57 Extension of venous thrombosis with pulmonary embolism and cases of phlegmasia cerulea dolens requiring amputation have also been reported. 1°'13'35'58-6° Thrombosis is most often loc- alised in the area with underlying vascular disease. 9

Bleeding complications of HIT are less frequent than

thrombotic complications, but serious bleeding may occur including retroperitoneal, intracere- bral, 14"21"32'35'45 gastrointestinal and postoperative haemorrhage. 22'23 Disseminated intravascular coagulation (DIC) has been occasionally reported. 27'42"61

The morbidity and mortality of HIT is dramatic. Patients are often critically ill at the time of the thrombotic episode as reflected by the reported morbidity rates of 22-80% and mortality rates of 12-30%. 21'23 The frequency of TEC in HIT can be reduced by careful patient monitoring, but mortality rates remain high once the complication occurs. 23

Contributing Factors

Source of heparin

Both bovine lung and porcine intestinal mucosal heparins have been implicated in most cases of HIT. However, drug induced thrombocytopenia and arterial thrombosis has also been diagnosed in patients treated with LMW heparins, 62'63 pentosan polysulphate, 64 and with a drug which resembles chondroitin sulfate (Arteparon). 65 It is not clear if heparinoid (Org 10172) can initiate type II HIT, but when given to patients who already have HIT caused by standard heparin, it can reactivate the syndrome. 34'61'62'66'67

Several prospective randomised studies have been conducted to compare the incidence of HIT caused by bovine and porcine heparin. 11'12'17"20'25'28'31-33"68 The majority of these studies revealed a higher incidence of HIT after administration of bovine heparin. War- kentin and Kelton 9"34 analysed five prospective randomised studies 17"25'28'31'68 and found that the incidence of HIT was approximately 1% for porcine mucosal and 5% for bovine lung heparin. Schmitt and Adelman 24 reported that the pooled incidence of HIT in studies requiring a reproducibly lower platelet count (< 100 000 mm 3) was 1.1% with intravenous porcine heparin and 2.9% with intravenous bovine heparin. The differences in chemical composition, platelet aggregating properties and purity of heparin from various sources may explain the difference.

Dose and route of administration

HIT occurs in patients treated with either therapeutic or prophylactic doses of heparin. 7'23'69"7° The risk of HIT appears to be significantly lower with subcuta- neous heparin than that seen with intravenous therapy. 24 However, type II HIT can be caused by small

Eur J Vasc Endovasc Surg Vol 11, April 1996

262 M. Dryjski and H. Dryjski

amounts of heparin used in heparin flushes (250-500 units per day) 29"39'71-73 and by heparin present on heparin-coated pulmonary artery catheters. 74'75 Thromboembolic and haemorrhagic complications of HIT are more common in patients receiving high-dose heparin. 23,3°

Pathogenesis

The pathogenesis of HIT is not entirely understood, but available data suggest that there are different mechanisms for type I and type II HIT. In both types, thrombocytopenia does not seem to be due to platelet lysis but rather aggregation. The findings supporting this theory is that both discontinuation of heparin therapy or addition of protamine cause a recovery of platelet counts, which is too rapid to be due to replacement from the bone marrow. In addition, thrombi found in the arteries and veins of patients with HIT and TEC are of "white clot" t~pe i.e. mainly composed of platelet aggregates. 6'7'42"44"54'61'75 It has been suggested that HIT is a manifestation of DIC caused by heparin. 27'47'76'77 However, in the majority of HIT cases DIC is not diagnosed and if it is, it can usually be attributed to the underlying disease.14,21,35,43,52, 7~80

Type I HIT

Heparin can cause a mild platelet activation and aggregation in platelet rich plasma obtained from animals and persons 4'5 who have never been exposed to heparin. 18'81"82 This in vitro platelet activation is more prominent with bovine heparin than with porcine heparin and is significantly reduced or even absent with LMW heparins and heparinoid. 34's3 Hepa- rin binds to platelets in a specific and saturable fashion with sufficiently low Kd for binding to occur at

84 85 therapeutic heparin concentrations. ' The greatest amount of binding has been found for heparin fractions with high molecular weight and most exten-

84 sive sulphation. It has been also shown that heparin enhances the effect of platelet aggregation by other stimuli such as ADP, arachidonic acid, immune complexes and bacterial products, s6 In addition, heparin at therapeutic concentrations incubated with hyperag- gregable platelets from patients with prosthetic valves or severe peripheral vascular disease sT's8 induced significant platelet aggregation in vitro.

The proaggregatory properties of heparin in vitro

disappear after neutralisation with protamine sulphate or digestion with heparinase. 7s'89'9° Thus, the effect of heparin on platelets is presumably accom- plished by heparin itself, rather than a contaminant. This direct effect of heparin on platelets occurs in humans in vivo as well 5'2°'44 and explains the lack of demonstrable circulatory antiplatelet antibodies typ- ical for type I HIT. It has been also suggested that type I HIT may be coincidental not causally related to heparin itself is or may partially result from the technical error of electronic platelet counters. 34

Type II HIT

Both clinical and laboratory evidence indicate that the severe, delayed onset heparin-induced thrombocytopenia is mediated by an immune mechanism. The evidence includes: (a) thrombocytopenia usually occurs 6-12 days after the first administration of heparin; (b) thrombocytopenia may occur within hours in patients who have previously been exposed to heparinl°'35; (c) a platelet aggregating factor is present in the IgG and IgM fractions of serum 8'45'52'79'91, (d) the platelet associated IgG fraction is often elevated during the thrombocytopenic phase. Several different mechanisms of interaction between platelets, IgG and heparin have been postu-

8 29 45 79 80 92 93 93 lated. ' . . . . . Kelton et al. suggested that heparin is first bound to the platelet surface by platelet proteins, subsequently anti-heparin IgG binds to the antigenic determinants on the heparin molecule. Finally9 IgG binds to the platelets via Fc II receptors, which initiates platelet activation. This activation can be blocked in vitro by monoclonal antibodies specific for the platelet Fc receptor. 93 Lynch and Howe 8° proposed that heparin binds to platelets, and by its negative charge induces a change in the platelet membrane, exposing an immunogenic substance. Anderson 94 postulated that heparin has two distinct roles in type II HIT. First, heparin binds to the platelet surface, exposing new antigenic determinants which elicits antibody binding and platelet activation through Fc receptor mediated platelet-platelet interaction. In addition, heparin exerts a non-specific proaggregatory effect which is related to its size and negative charge. Recently9 Amiral et al. 95 proposed the involvement of platelet factor 4 in the platelet binding of heparin-dependent antibodies. Visentin et al. 91 confirmed these results and found that platelet activat- ing, heparin-induced antibodies are specific for platelet factor 4/heparin complexes.

The duration of heparin-dependent IgG is



unknown, but once heparin therapy is discontinued antibody levels slowly decrease over a period of several months, with concomitant loss of heEarin- induced platelet aggregation in vitro. 18"29"48"59"71"90"96

Several patients have been re-exposed to heparin after 1 to 4 months and have not developed recurrent HIT. 8"16"21"45'96 However, persistent heparin sensitivity 28 months and 7 years respectively after recovery from HIT have been reported. 23'97 Early re-exposure to heparin after HIT may sometimes be disastrous, in three reported cases the patients developed massive pulmonary embolism and died within 30 min. 13'~8"5°

Pathophysiology of heparin induced thrombosis

The pathophysiology of heparin induced thrombosis is not well known. There is no clinical sign, nor laboratory test which allows prediction of thrombembolic complication in patients with HIT. Some clinical observations indicate that thrombi occur more frequently at sites of pre-existing vascular disease or endothelial damage, caused by balloon catheter used for thromboembolectomy or recent arterial puncture

43 58 for heart catheterisation. • Thus, the integrity of the vascular endothelium could be an important factor in the development of TEC in HIT. Cines et al. 98 demonstrated that heparin antibodies bind to cultured endothelial cells and promote expression of tissue factor in the cells in the absence of heparin. Recently, Visentin et al. 91 suggested that antibodies associated with HIT may react with platelet factor 4 complexed with heparan sulfate on the surface of endothelial cells leading to antibody-mediated endothelial injury and a predilection to thrombosis.

Diagnosis

HIT should be suspected in patients with thrombocytopenia which occurs during heparin therapy and resolves after withdrawal of heparin. It is, however, important to remember that HIT is primarily a clinical diagnosis of exclusion, particularly in patients who also receive several other drugs and /or have co- morbid conditions such as sepsis, disseminated intravascular coagulation, idiopathic thrombocytopenia purpura and bone marrow failure.

Coagulation tests may distinguish heparin-induced platelet aggregation from other clotting disorders, since in HIT fibrinogen and fibrin split product levels as well as prothrombin time are usually normalY '~6'54

When HIT is suspected, laboratory tests for the presence of heparin-dependent platelet antibodies should be performed.

Laboratory Tests for HIT

A large number of laboratory tests for heparin dependent platelet antibodies have been descr ibed. 8'14'16'39'42'48"64'74"99-103 Warkentin and Kel- ton 9 divided these tests into three groups. Group I assays measure a platelet dependent endpoint such as aggregation, serotonin release or platelet factor III activity initiated by test serum and heparin. 16'39"48"99 Group II tests measure he~arin dependent binding of IgG to normal platelets. 14'42'64"1°° Group III assays measure heparin dependent binding of patient IgG to individual platelet glycoproteins. 8°'1°1 In clinical prac- tice only three methods are commonly used: platelet aggregometry, 14C-serotonin release and platelet associated IgG tests. The most frequently used test is the aggregation of normal donor platelets by patient serum or plasma in the presence of heparin. This method is inexpensive, relatively simple and highly specific (>92%). 16 However, the sensitivity of the aggregometry assay may vary widely between 40% and 80% depending on the donor, whose platelets were used in the test. I°4 Therefore, a panel of four or more donors should be used in order to improve the test sensitivity. The most sensitive and specific test is probably the one described by Sheridan et al. 99 It is an assay that measures 14C serotonin release from washed donor platelets using heat treated patient serum in the presence of therapeutic (0.1 U/ml) and high (100 U/ml) heparin concentrations. If serotonin release occurs at therapeutic but not high heparin concentration, the test is positive. The test is negative if platelet release occurs at both heparin concentrations or if it fails to occur. The specificity of the assay is about 99% and sensitivity approximately 80%.

Development of new and modification of old assays have been reported in the past few years. Greinacher et al. 1°5 described a rapid assay based on visual evaluation of heparin induced platelet activation in microtitre wells. The sensitivity of this new test is supposed to be similar to 14C serotonin release and superior to platelet aggregometry assay. 1°5 Amiral et al. 95 reported an ELISA assay for heparin induced antibodies based on their reaction with immobilized complex of heparin and platelet factor 4. Visentin et

91 al. modified this assay and found it remarkably sensitive.



Table 1. General guidel ines for prevent ion of hepar in induced heparin thrombocytopenia in patients not previously k n o w to have hepar in- induced ant ibodies

A. Heparin of porcine intestinal origin should preferably be used. B. The duration of heparin therapy should be minimised whenever

possible. C. In patients who need prolonged anticoagulation oral

anticoagulants should be started within 24 h of initial heparin therapy.

D. For DVT prophylaxis and treatment LMW heparin is a better choice than unfractionated heparin.

E. Use pure saline or sodium citrate flushes instead of heparin to maintain patency of intravascular catheters.

F. Obtain a complete blood count before initiation of heparin therapy and then platelet count every third day.

G. If an unexplained decline in the platelet count of more than 30% occurs, a test for the presence of heparin-dependent antibodies should be performed.

Prevention

Prevention of HIT in patients previously not known to have the disorder is unrealistic, however some guidelines have been developed to minimise the risk of HIT. These are summarised in Table 1. The general rule is that heparin should be used only in well documented cases with clear indication for i.v. anticoagulation. Thus, the use of heparin flushes to maintain patency of intravascular catheters should be eliminated, since it can be successfully replaced with pure saline or sodium citrate flushes, m6 Patients who require prolonged therapeutic anticoagulation, but for different reasons cannot take oral anticoagulants should be treated with LMW heparin or heparinoid rather than unfractionated heparin. In these patients, platelet counts should be obtained weekly. Finall)~ it is important to remember that thrombembolic complications in patients with HIT are often devastating but unfortunately can not be predicted by any test.

Treatment

The following guidelines have been recommended when the platelet count falls 30% or moreg: (a) repeat platelet count; (b) investigate for other possible causes of thrombocytopenia; (c) perform assay of heparin- dependent antibodies; (d) re-evaluate the need for heparin treatment. It may not be necessary to dis- continue therapy in cases of mild thrombocytopenia with negative tests for heparin-dependent antibodies since type I HIT often resolves even with continuation of heparin treatment. However, it is difficult to differentiate between type I and the early stages of type II HIT and therefore, if heparin has to be continued it is mandatory to monitor closely the

patient's condition and perform platelet counts daily. If there are any clinical signs of TEC or if laboratory tests indicate type II HIT, heparin therapy should be discontinued immediately and alternative therapy should be considered. Some authors 56 recommend reversal of heparin with protamine sulfate, but in the majority of patients, cessation of heparin results in rapid recovery of the platelet count. If the patient's condition requires continuation of anticoagulation, substitution with vitamin K antagonist has been recommended. 9"13'21'23'35'41'49'96 Sometimes other therapeutic modalities must be employed in the interim period before anticoagulants become effective. Several agents such as LMW heparin, heparinoids, synthetic thrombin inhibitors, Dextran, Iloprost, acetylsalicylic acid, sulfinpyrazone, Ancrod, plasmapheresis, immunoglobulin and fibrinolytic therapy have been used with variable results. Although, the optimal therapy for patients with HIT remain uncertain, some of the drugs which have been used for treatment of HIT are reviewed below.

Low molecular heparin and heparinoids

There has been a growing interest in treatment of HIT with LMW heparin and heparinoids. The clinical

42 58.61 66 67 83 88 107 110 outcome has been variable. ' . . . . . . - In the cases with a negative cross-reactivity test in vitro, the clinical outcome was favourable, but a positive platelet aggregation test was sometimes associated with unfavourable clinical outcome. 6~'1°7 The cross reactivity rate of different LMW heparin preparations varies between 25 and 90% 63,66,67 The heparinoid Org 10172 has not been found to promote heparin-induced non-immune aggregation and has shown a low frequency (10%) of cross-reactivity in vitro with sera containing heparin-dependent antibodies. 58'66'67'111-113 Magnani reviewed international'experience with the use of Org 10172 in 230 patients with HIT for which urgent anticoagulation was necessary. 67 Ninety-three percent of patients adequately responded to Org 10172, nevertheless, the mortality rate was 26% of which 3% was directly attributed to Org 10172 use. Experience with Org 10172 is still limited and the results of prospective, randomised studies should be made available before Org 10172 can be recommended as a treatment of choice for the patients with HIT.

Antiplatelet agents

Antiplatelet agents such as aspirin, dipyridamole and



dextran block the second phase of platelet aggregation. Aspirin has been utilised with some success in treatment of HIT 96'114'115 and as a prophylaxis against HIT when patients need to be re-exposed to heparin. 23'39"116'117 Several investigators have reported quicker and safer recovery in patients treated with aspirin or dextran. 96"114'11s Iloprost, a prostacyclin analogue with half-life of 15-20 rain has been successfully used for treatment of patients with HIT requiring re-exposure to heparin. 39'97"~18

Defibrinogenating agents

The snake venom Ancrod is a defibrinogenating agent with rapid onset of anticoagulant activity. Ancrod acts enzymatically to cleave fibrinogen to split off fibrinopeptide A but not fibrinopeptide B, to produce unstable non-cross-linked fibrin which is rapidly lysed. It lacks immunological cross-reactivity with heparin and is relatively simple to monitor by measur- ing the fibrinogen level. 34 Ancrod antidote is available and restores plasma fibrinogen levels within an hour. 119 This agent has been successfully used in Canada and the United States for patients who require rapid anticoagulation, open heart surgery or vascular surgery. ~9,12°

Other therapies

Although controversial, streptokinase and urokinase treatment has been successful in several cases of HIT with TEC. 51'61A21-123 Plasmapheresis has been used in a few patients with HIT and thrombosis. 124 The aim of this procedure is to remove circulating heparin- dependent IgG but it is unclear if such treatment can significantly improve the clinical outcome. One case of type II HIT with gastrointestinal bleeding treated successfully with immunoglobulin has been reported. 12s However, it was unclear if recovery was due to immunoglobulin infusion or solely cessation of heparin treatment. Finall)~ patients with type II HIT requiring a haemodialysis have been treated with the synthetic thrombin inhibitor Argatroban. 126'127 Arga- troban shows no cross-reactivity with heparin- dependent antiplatelet antibodies and inhibits heparin-induced platelet aggregation. 126 Platelet transfusions sometimes used for treatment of HIT with bleeding complications ~28 are generally not recommended as acute arterial thrombosis can O c c u r . 48,52

Treatment of HIT with Thromboembolic Complications

When HIT with acute thrombosis is diagnosed, heparin treatment should be immediately discontinued. The treatment of choice for arterial thrombosis should be surgical. 34 Heparin should not be used perioperatively, but dextran and/or aspirin alone or in combination with dipyridamole is recommended. Oral anticoagulant treatment should be given as soon as possible. Iloprogt perioperatively or Ancrod management in an interim period may also be considered. 6°'12° The experience of several investigators indicates that if heparin is given during operation for HIT thrombosis, the procedure fails, whereas patients not re-exposed to heparin usually have a successful

9 21 60 outcome. ' ' Streptokinase or urokinase treatment of arterial thrombosis in patients with HIT has been used successfully in the number of patients. 9'51'121 Throm- bolytic therapy should be also considered for the treatment of extensive deep venous thrombosis with pulmonary embolism, s1"61'12~'122

Management of Patients who Require Re-exposure to Heparin

Traditionally all patients undergoing cardiopulmonary bypass, carotid endarterectomy, femorodistal bypass operation and haemodialysis are given heparin. Patients with a history of HIT have a higher risk for postoperative morbidity and mortality and therefore benefits of surgery should be carefully balanced against the risk of potentially dangerous exposure to heparin. The experience from several centres indicates that patients without demonstrable heparin-dependent IgG usually tolerate a short re-exposure to heparin. 9'96 Heparin treatment in such cases should be limited as much as possible and heparin flushes as well as heparin coated catheters should not be used.

Patients requiring urgent cardiac or vascular surgery despite circulating heparin-dependent IgG repre- sent a difficult clinical problem. Preoperative administration of aspirin and dipyridamole 116'117'128 or intraoperative infusion of Iloprost 97'118'128'129 allowed successful operation in several reported cases. Kappa et al. suggested that Iloprost is both safer and more effective than aspirin in treatment of these patients. 97 Ancrod has been used as an alternative to heparin in patients with HIT requiring surgery. The reported

119 120 130 experiences are encouraging. ' ' LMW heparin and particularly Org 10172 alone have also been used successfully in cases where cross-reactivity in vitro was not found . 66'67'131



The incidence of HIT in patients requiring haemodialysis is unknown. These patients are frequently re- exposed to heparin and occurrence of HIT could be a significant clinical problem. There are a few reports on successful treatment of these patients with aspirin, 132-134 p rostacyclin, 135 Org 1017293"94'136 and Argo- troban. 126'127 In some cases heparin free haemodialysis has been u s e d . 133'135'137

Deep vein thrombosis in pregnancy is one of the situations where prolonged treatment with heparin is often required. A few cases of HIT in pregnancy have been reported. 67'13s-141 In two patients, HIT resolved after changing to a different brand of heparin, 13s'14° another patient developed recurrent HIT after prolonged treatment with Org 10172.142 Van Besien et

al. ~42 recommended that pregnant patients with HIT should be treated with Org 10172 only in the first trimester, in the second and third trimester they could be treated with oral anticoagulants with minimal risks. 143

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Accepted 7 June 1995


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