Heparins

Hemorrhage

The major adverse reaction to heparin is bleeding, which can occur with both low molecular weight and unfractionated heparin [ ]. The EIDOS and DoTS descriptions of heparin-induced bleeding are shown in Figure 1 .

Frequency . An authoritative review of the relevant literature was published in 1993 and is still valid [ ]. Its authors concluded that the use of heparin in therapeutic dosages (over 15 000 IU/day) is typically marked by an average daily frequency of fatal, major, and major and minor bleeding episodes of 0.05%, 0.8%, and 2.0% respectively; these frequencies are about twice those expected without heparin therapy. In 2656 medical patients studied by the Boston Collaborative Drug Surveillance Program, the crude risk of bleeding from heparin (route unspecified) was 9% but varied with dose: 4.9% for doses below 50 IU/kg per dose, 8.1% for doses of 50–99 IU/kg per dose, and 17% for doses of 100 IU/kg per dose or more [ ]. The 7-day cumulative risk for any kind of bleeding was 9.1%. Melena, hematomas, and macrohematuria were the most frequent manifestations; intracranial bleeding and pulmonary bleeding were rare.

Presentation . In the Boston Collaborative Drug Surveillance Program study mentioned above [ ], the localization of bleeding, expressed in percentages and broadly classified as major/minor, was as follows:

• gastrointestinal hemorrhage 49/11;

• vaginal hemorrhage 11/8 (1/3 postpartum);

• bleeding from wounds and accidental soft-tissue trauma 11/28;

• retroperitoneal bleeding 6/0;

• genitourinary bleeding other than vaginal 6/35;

• intracranial hemorrhage 5/0;

• epistaxis 4/10;

• other forms of blood loss 8/8.

An FDA Health Advisory warning was issued in December 1997 after 30 cases of spinal hematoma had been reported in patients undergoing spinal or epidural anesthesia while receiving low molecular weight heparin perioperatively. In the European literature, the risk of spinal hematoma in patients receiving low molecular weight heparin was not considered clinically significant. In Europe, low molecular weight heparin is given once a day and at a smaller total daily dose; this enables the placement (and removal) of needles and catheters during periods of reduced low molecular weight heparin activity. Identification of further susceptibility factors is difficult, owing to the rarity of spinal hematomas. However, several possible susceptibility factors have been suggested: about 75% of the patients were elderly women, in 22 patients an epidural catheter was used, and in 17 patients the first dose of low molecular weight heparin was administered while the catheter was indwelling; 12 patients received antiplatelet drugs and/or warfarin in addition to low molecular weight heparin [ ]. The authors formulated recommendations for minimizing the risk of spinal hematoma, including using the smallest effective dose of low molecular weight heparin perioperatively, delaying heparin therapy as long as possible postoperatively, and removing catheters when anticoagulant activity is low. Furthermore, they warned against combining low molecular weight heparin with antiplatelet drugs or oral anticoagulants.

Relation to dose . Subgroup analyses of randomized trials and prospective cohort studies point to an association, as one would expect, between the incidence of bleeding and the anticoagulant response as measured by a test of blood coagulation, for example the activated partial thromboplastin time (APTT). For instance, there were five major bleeding episodes in 10 patients whose APTT was prolonged to more than twice the upper limit of their therapeutic range but only one episode in 40 patients whose APTT remained in the usual target range (RR = 20) [ ]. Furthermore, there is an increased rate of major bleeding with intermittent intravenous use compared with continuous intravenous heparin infusion. Differences in major bleeding are not generally detected between continuous intravenous and subcutaneous heparin [ ].

Time - course . In the Boston Collaborative Drug Surveillance Program study mentioned above, the peak incidence of bleeding was on the third day after the start of heparin therapy, which suggests a relatively safe initial 48-hour period in systemic heparinization [ ]. However, bleeding can be expected at any time during therapy, if the dosage becomes excessive or if susceptibility factors, such as trauma, intervene.

Susceptibility factors . In the Boston Collaborative Drug Surveillance Program study mentioned above, bleeding correlated with aspirin treatment, with sex, and probably with age and renal function [ ]. A meta-analysis of randomized trials reported that those aged over 70 are associated with a risk of major bleeding [ ]. Recent surgery or trauma also increase the risk.

Low molecular weight heparin versus unfractionated heparin . Because of its reduced activity on overall clotting, low molecular weight heparin is expected to cause less bleeding than unfractionated heparin. However, several meta-analyses of randomized comparisons of low molecular weight heparin with unfractionated heparin in the prevention of postoperative deep venous thrombosis showed no difference in the incidences of major bleeding [ , ]. For low molecular weight heparin, the rates of major bleeding ranged from 0% to 3% and fatal bleeding from 0% to 0.8%. A later meta-analysis of randomized comparisons in the initial curative treatment of deep venous thrombosis showed a 35% reduction in major bleeding in patients treated with low molecular weight heparin, but this result was not significant [ ].

Enoxaparin is not associated with more major hemorrhagic complications in unselected medical patients than in controlled trials. In a prospective observational study of 549 consecutive patients who received enoxaparin 1 mg/kg bd for at least 24 hours (mean duration of therapy 3.8 days), there was hemorrhage in 94 (17%). There was major hemorrhage in 14 (2.6%), injection-site hemorrhage in 55 (10%), and minor (non-injection site) hemorrhage in 25 (4.7%) [ ]. Two deaths were attributed to hemorrhage. Patients with major hemorrhage were older than patients with minor or no hemorrhage (76 versus 67 years). Major hemorrhage occurred in patients who received enoxaparin for a longer period (mean 5.1 days) than those with minor hemorrhage (4.0 days) or none (2.9 days). Major haemorrhage was significantly associated with impaired renal function, chronic liver disease, and concomitant treatment with warfarin or a proton pump inhibitor.

Symptomatic hemorrhagic transformation is common in supratentorial and cerebellar infarction, but is rare in brainstem infarction and is seldom reported in basilar artery occlusion. Although early arterial recanalization by thrombolytic agents has been widely used after cerebral infarction, some neurologists still prefer to use an anticoagulant in patients with basilar artery occlusion, especially in longer-existing ischemic deficits. However, massive pontine hemorrhage has been associated with enoxaparin in a patient with basilar artery occlusion [ ].

Of 52 randomized controlled trials of prophylaxis of deep vein thrombosis, 33 quantified the bleeding complications in 33 813 patients undergoing general surgery [ ]. Of the minor complications, injection site bruising (6.9%), wound hematoma (5.7%), drainage site bleeding (2.0%), and hematuria (1.6%) were the most common. Major bleeding complications, such as gastrointestinal tract bleeding (0.2%) or retroperitoneal bleeding (> 0.1%), were infrequent. Withdrawal was required in 2.0% of patients and subsequent operation in less than 1%. When analysed by high-dose versus low-dose unfractionated heparin, the lower dose had a smaller rate of withdrawal and subsequent operation.

The OASIS-5 study (Organization to Assess Strategies for Ischemic Syndromes) randomized 20 078 patients with non-ST-segment elevation acute coronary syndrome to subcutaneous fondaparinux 2.5 mg/day or enoxaparin 1 mg/kg for up to 8 days [ ]. There was more major bleeding with enoxaparin (4.1% versus 2.2%), including fatal bleeding (22 versus 7 events).

Endocrine glands are highly vascularized, but non-traumatic hemorrhage is extremely rare.

• A 63-year-old woman developed an acute painful mass in the neck due to a massive thyroid hematoma while she was receiving low-molecular-weight heparin for deep vein thrombosis [ ]. This was followed by an increase in serum free thyroxine and free triiodothyronine concentrations and a fall in the concentration of serum thyroid-stimulating hormone (thyrotropin). Heparin was withdrawn and no antithyroid therapy was necessary. The serum thyroid hormone concentrations fell into the reference ranges as the hematoma shrank.

Thrombocytopenia

The EIDOS and DoTS descriptions of heparin-induced thrombocytopenia type II are shown in Figure 2 .

Thrombocytopenia (100 × 10 ⁹ /l or lower) occurs in about 3–7% of patients, independent of the mode of administration or the dose and type of heparin [ , ]. The incidence varies largely among published series, but the overall average may be some 5% [ ]. There was a higher incidence in some older studies [ ], but this may have been due to the presence of impurities in the heparin then available, and some of the studies clearly included cases of thrombocytopenia not attributable to heparin. Even currently the incidence is to some extent uncertain, because of differences in methods of diagnosis and in the definitions used [ , ]. Low molecular weight heparin is significantly less likely to cause thrombocytopenia than unfractionated heparin [ ].

Heparin-induced thrombocytopenia [ ] has been recognized in adults for some time, and more recently in neonates and children [ ]. There are two types. Type I is non-immunogenic, mild, and self-limiting. Type II is less common but is a severe immune reaction that often leads to thromboembolic complications; it is generally seen after a week or more of treatment. A third variety, so-called “delayed-onset heparin-induced thrombocytopenia” has also been described.

In 12 patients, recruited from secondary and tertiary care hospitals, thrombocytopenia and associated thrombosis occurred at a mean of 9.2 (range 5–19) days after the withdrawal of heparin; nine received additional heparin, with further falls in platelet counts [ ].

In a retrospective case series, 14 patients, seen over a 3-year period, developed thromboembolic complications a median of 14 days after treatment with heparin [ ]. The emboli were venous (n = 10), or arterial (n = 2), or both (n = 2); of the 12 patients with venous embolism, seven had pulmonary embolism. Platelet counts were mildly reduced in all but two patients at the time of the second presentation. On readmission, 11 patients received therapeutic heparin, which worsened their clinical condition and further reduced the platelet count.

Heparin can rarely cause acute cardiorespiratory reactions, and some reports relate this to underlying heparin-induced thrombocytopenia. Over 2 years four cardiovascular surgery patients were identified who had eight episodes of cardiorespiratory collapse immediately after heparin administration; all had underlying heparin-induced thrombocytopenia [ ]. They received intravenous boluses of unfractionated heparin. Two had severe respiratory distress within 15 minutes, for which they required endotracheal intubation. Two others had a cardiac arrest or a dysrhythmia within minutes of receiving intravenous heparin. Serological tests for heparin-induced antibodies were positive in all cases. In three cases, the platelet count was normal or near normal, but fell dramatically immediately after the heparin bolus. Three patients had prior diagnoses of heparin-induced thrombocytopenia, but their prescribers gave them heparin either unaware of the diagnosis or ignorant of its significance. The authors noted that heparin administration to patients with heparin-induced antibodies can result in life-threatening pulmonary or cardiac events.

A spinal-epidural hematoma occurred after combined spinal–epidural anesthesia in a woman who had been taking clopidogrel and had received perioperative dalteparin for thromboprophylaxis [ ]. This occurred despite adherence to standard guidelines on the administration of low-molecular-weight heparin perioperatively and withdrawal of clopidogrel 7 days before the anesthetic.

• A 44-year-old woman developed delayed-onset thrombocytopenia and cerebral thrombosis 7 days after a single dose of standard heparin 5000 units [ ].

Type I heparin - induced thrombocytopenia . Type I heparin-induced thrombocytopenia is common and is characterized by a mild transient thrombocytopenia (with platelet counts that usually do not fall below 50 × 10 ⁹ /l); the thrombocytopenia occurs on the first few days of heparin administration (usually 1–5 days) and requires careful monitoring but not usually withdrawal of heparin. Type I thrombocytopenia is a non-immune reaction, probably due to a direct activating effect of heparin on platelets, causing aggregation. It is generally harmless. Thrombocytopenia is most common when large doses of heparin are used, or in some particular circumstances, such as after thrombolytic therapy [ ] or in the early orthopedic postoperative period [ ]; it can abate in spite of continued therapy.

Type II heparin - induced thrombocytopenia . Type II heparin-induced thrombocytopenia is less common than type I, but it is often associated with severe thrombocytopenia. It is generally accepted that heparin-induced thrombocytopenia refers to platelet counts of less than 150 × 10 ⁹ /l or a reduction in platelet count to 30–50% of a previous count. In some cases, platelet counts that have fallen to 50% from a high normal previous count would remain apparently normal but should be considered as potentially heparin-induced thrombocytopenia.

The literature on heparin-induced thrombocytopenia has been reviewed in the context of a case in a neonate after heart surgery [ ].

Incidence The incidence of type II thrombocytopenia is 2–5% in adults and may be equally high in neonates and children; it is about 6.5% in patients receiving unfractionated heparin after orthopedic surgery and 1% or less in other settings [ ].The mortality rate in adults is 7–30% and is unknown but potentially high in neonates. Its occurrence depends on the definition of HIT, the type of heparin used (bovine unfractionated > porcine unfractionated > low molecular weight heparin), the duration of administration (the risk being highest on days 5–14), the patient’s sex (female > male), and the type of test used to detect heparin-dependent antibodies.

The most frequently suspected drug registered by the German spontaneous reporting system in cases of thrombocytopenia was unfractionated heparin [ ]. Of 3291 adverse reactions reports, 78% were associated with unfractionated heparin, 13% with enoxaparin, 11% with certoparin, 5.5% with dalteparin, 2.8% with heparin fractions, 2.5% with reviparin, and 1.2% with tinzaparin. Heparin-induced thrombocytopenia was the most common adverse effect (38%), followed by pulmonary embolism (11%), hematomas (6.8%), erythematous rashes (4.8%), and unspecified bleeding (4.5%). Injection site reactions were common (15%) and included skin necrosis and injection site necrosis in 1.8% of cases. Antibodies to heparin–platelet factor 4 (PF4) complex can be demonstrated in almost all patients with type II heparin-induced thrombocytopenia. There was a positive specific antibody result in 736 (59%) of 1245 cases.

The incidences of heparin-induced thrombocytopenia in surgical and medical patients receiving thromboprophylaxis with either unfractionated or low-molecular-weight heparin have been studied in a systematic review of all relevant randomized and non-randomized studies identified in MEDLINE (1984–2004), not limited by language, and from reference lists of key articles [ ]. Heparin-induced thrombocytopenia was defined as a fall in platelet count to less than 50% or less than 100 × 10 ⁹ /l and a positive laboratory diagnostic assay, including enzyme-linked immunosorbent assay (ELISA), [ ¹⁴ C]serotonin release assay, or adenosine triphosphate lumi-aggregometry. There were 15 eligible studies (7287 patients).

The odds ratios were as follows:

• two randomized controlled trials (n = 1014): OR = 0.10 (95% CI = 0.01, 0.2);

• three prospective studies with non-randomized comparison groups (n = 1464): OR = 0.10 (95% CI = 0.03, 0.33);

• all 15 studies (including ten in which only thrombocytopenia was measured): OR = 0.47 (95% CI = 0.22, 1.02).

The absolute risks were 0.2% with low-molecular-weight heparin and 2.6% with unfractionated heparin.

In a retrospective study of 389 consecutive patients with subarachnoid hemorrhage, 59 (15%) met the clinical diagnostic criteria for heparin-induced thrombocytopenia type II [ ]. The average platelet count nadir was 69 × 10 ⁹ /l. Women and patients with Fisher Grade 3 were at higher risk. There were systemic thrombotic complications in 37% compared with 7% of those without thrombocytopenia. There were more new hypodensities on CT scan in those with thrombocytopenia (66% versus 40%) and more deaths (29% versus 12%).

In a retrospective analysis of 1017 consecutive samples tested for antibodies by enzyme-linked immunosorbent assay and for platelet function by 5HT release, most of the samples showed no serological evidence of HIT, but4–5% of samples showed both antigenic and functional serological evidence of HIT; 12–18% of samples showed immunological evidence of PF4/heparin antibodies but without functional evidence of 5HT release in vitro [ ]. A small minority of samples (0.7%) caused 5HT release but were negative for antibodies.

A polymorphism of platelet GPIIIa (PlA2, also called HPA1b) has been associated with a higher risk of thrombosis. In 66 consecutive patients with a laboratory diagnosis of HIT, thrombotic complications developed in 27 (41%) and were more likely in patients with the PlA2 (69% versus 32%; OR = 4.7; 95% CI = 1.4, 16) [ ].

In a retrospective case–control study in 210 patients in a surgical ICU who had HIT antibody assays performed, 19 (9%) had positive tests [ ]. Compared with 19 matched controls, the HIT antibody-positive patients had an increased risk of death or major thrombotic complications (7 versus 2), and a prolonged length of stay in the ICU (20 days versus 10 days). Exposure to heparin via intravascular flushes alone was sufficient to generate HIT antibodies in 12 of 19 patients. Five patients received platelet transfusions after the diagnosis of HIT was made; four of them died.

Dose relation Heparin-induced thrombocytopenia can occur after minimal heparin exposure, including heparin flushes [ ]. It is therefore a hypersusceptibility reaction.

Time - course The fall in platelet count usually occurs 5–10 days after the first exposure to heparin.

Thrombocytopenia has been reported in a patient who received intraperitoneal heparin [ ].

• A 52-year-old man with end-stage renal disease and peritonitis associated with CAPD was given intraperitoneal heparin 1000 U/day for 7 days. His platelet count 13 days before this had been 260 × 10 ⁹ /l, but 14 days after the last dose of heparin he developed epistaxis and petechiae on his trunk and lower legs and the platelet count was 25 × 10 ⁹ /l. His platelet count spontaneously normalized over the next 7 days.

Heparin-induced thrombocytopenia was confirmed by detection of antibodies against the heparin–PF4 complex using a serotonin release assay.

Thrombosis can occur when heparin causes a fall in the platelet count within the reference range if there are associated antibodies [ ].

• A 45-year-old man with pulmonary embolism was given heparin and developed massive thrombosis after insertion of a filter on day 3; the platelet count was 221 × 10 ⁹ /l. Heparin was replaced by argatroban on day 13 and the platelet count rose to 355 × 10 ⁹ /l on day 15. There were antibodies against complexes of heparin and platelet factor 4.Since 1992, miniaturized pulsatile air-driven ventricular assist devices, the so-called “Berlin Heart”, have been used in children at many institutions (36 cases in North America in 19 different institutions). Heparin-induced thrombocytopenia can cause thrombosis in such devices [ ].

• A 13-month-old girl, weight 8.1 kg, who required support with a left ventricular assist device for cardiogenic shock of unclear cause, developed a persistent low-grade fever, heparin-induced thrombocytopenia, and impaired renal function. On post-implant day 10, the pump required replacement because of concerns about an inlet valve thrombus; the explanted device contained a nearly occlusive clot.

Mechanism Type II thrombocytopenia is probably an immune-mediated phenomenon, a fact that has been the subject of much specific investigation [ , ]. It has been proposed that the diagnosis should depend on two criteria: the association of one or more clinical events and laboratory evidence of a heparin-dependent immunoglobulin [ ]. In 389 patients with HIT type II, 351 patients with thrombocytopenia or thrombosis due to other causes than HIT, and 256 healthy blood donors, the platelet Fcγ-receptor polymorphism FcγRIIa-R-H131 was over-represented in the patients with HIT (27%) compared with the other two groups (21% and 20% respectively); in a subgroup of 122 well-characterized patients with HIT, the frequency of FcγRIIa-R-H131 among those with thrombotic events was significantly increased compared with those without such complications (37% versus 17%) [ ]. The authors speculated that reduced clearance of immune complexes in patients with the FcγRIIa-R-H131 genotype causes prolonged activation of endothelial cells and platelets, increasing the risk of thrombotic complications.

Presentation Heparin-induced thrombocytopenia usually occurs with a delayed onset (a week or more) and is often complicated by paradoxical recurrence of thromboembolic events, leading to life-threatening complications. The general term “heparin-induced thrombocytopenia” is as a rule used to designate this phenomenon.

Thrombosis can occur before the onset of overt thrombocytopenia [ ]. In some cases dramatic thrombotic events occur in association with antibodies without significant fall in platelet count [ ]. Thrombotic complications include new or recurrent arterial thromboembolism, often localized in the distal aorta and legs or presenting as myocardial infarction and hemiplegia [ ], but also in the brachial artery [ ], often requiring surgical treatment. In older reports there was a higher incidence of arterial than of venous thrombosis, but later reports documented that venous thrombosis is four times more common than arterial thrombosis [ ]. Heparin-induced thrombocytopenia can be associated with deep venous thrombosis and pulmonary embolism, but unusual forms of thrombosis, such as adrenal hemorrhagic infarction due to adrenal vein thrombosis, a complication that must be considered in patients who develop abdominal pain or unexplained hypotension during heparin therapy, are not uncommon.

Thrombocytosis in a patient receiving enoxaparin did not occur with unfractionated heparin [ ].

• A 42-year-old man was given enoxaparin for 8 days and developed thrombocytosis. Enoxaparin was switched to unfractionated heparin and the platelet count normalized within 6 days. Enoxaparin was restarted and the platelet count rose and peaked after 8 days at 920 × 10 ⁹ /l.

Venous limb gangrene due to heparin-induced thrombocytopenia is characterized by distal tissue losses, with extensive venous thrombosis involving large veins and small venules [ ]. This reaction seems to be related to acquired deficiency of protein C induced by concomitant oral anticoagulants.

Patients with heparin-induced thrombocytopenia have a reported mortality of 25–30% and amputation rates of up to 25% [ ]. The development of the syndrome is not related to the dose of heparin in the therapeutic range (that is it is a hypersusceptibility reaction). This has been confirmed by the fact that thrombocytopenia with thromboembolic complications sometimes occurs after the limited exposure that is involved in “flushing” with heparin and saline to maintain the patency of venous catheters [ ].

Heparin-induced skin necrosis is an immune-complex phenomenon associated with heparin-induced thrombocytopenia (HIT); it can rarely occur in the presence of HIT IgG alone (serological HIT). It is thought to be caused by an antibody-mediated local prothrombotic condition associated with platelet activation and increased thrombin production. If skin necrosis occurs, treatment with an alternative thromboprophylactic agent should be considered. See also below under Skin.

New or recurrent venous thromboembolism can occur in patients who receive heparin if immune-mediated heparin-induced thrombocytopenia occurs. There has been a comprehensive, systematic literature search for studies of the use of unfractionated or low-molecular-weight heparin for thromboprophylaxis or treatment in which new or recurrent venous thromboembolism and serologically confirmed heparin-induced thrombocytopenia were reported [ ]. Ten studies were identified, involving intravenous unfractionated heparin, subcutaneous unfractionated heparin, or subcutaneous low-molecular-weight heparin. There was venous thromboembolism in 386 of 6219 patients, including 32 who also had heparin-induced thrombocytopenia. There was no difference between intravenous and subcutaneous unfractionated heparin (13% versus 12%; OR = 1.07; 95% CI = 0.50, 2.3), but a significant difference between unfractionated heparin and low-molecular-weight heparin (13% versus 0.7%; OR = 21; 95% CI = 2.8, 156).

• A 27-year-old woman at 8 weeks gestation developed a cerebral venous thrombosis involving the superior sagittal, rectus, and right transverse sinuses and was given intravenous unfractionated heparin [ ]. One week later, her clinical condition having improved, she was switched to enoxaparin 6000 units bd but soon after had a pulmonary embolism and was given intravenous heparin. Nine days later her platelet count fell from 307 to 111 × 10 ⁹ /l. Her platelet factor 4-heparin enzyme immunoassay was positive. Heparin was withdrawn and she was given intravenous lepirudin 0.15 mg/kg/hour. Her platelet count recovered within 1 week.

• A 43-year-old woman with myasthenia gravis underwent plasma exchange, during which a Gamcath central venous line was locked with heparin 5000 U/ml between procedures; 12 days later she developed type II heparin-induced thrombocytopenia complicated by iliofemoral deep venous thrombosis and pulmonary embolism [ ]. Serology for heparin/PF4 antibodies was positive. The line was removed and she was successfully managed with intravenous lepirudin.

Catastrophic antiphospholipid syndrome is a medical emergency characterized by thrombosis of multiple small vessels of the internal organs and the brain [ ]. In one case hepatic, renal, and splenic artery thromboses, as well as cerebral venous thrombosis, were complicated by severe thrombocytopenia and hemolytic anemia. However, there were no anti-platelet-factor-4 antibodies, making heparin-induced thrombocytopenia unlikely.

Management HIT should be suspected whenever the platelet count falls by more than 50% from baseline or to below 150 × 10 ⁹ /l, 5–14 days after starting heparin (or sooner if there was prior heparin exposure), or if new thrombosis occurs during or soon after heparin treatment, other causes having been excluded.

When HIT is suspected, heparin should be immediately withdrawn and an alternative anticoagulant used. Platelet counts usually return to normal within 2–3 days of withdrawal of heparin, much faster than after early-onset thrombocytopenia. Rechallenge with heparin leads to an abrupt fall in the number of platelets and to reappearance of the clinical signs and symptoms, sometimes leading to sudden death [ ].

From the therapeutic point of view, prophylaxis of thrombosis must be continued after withdrawal of heparin, since even when there is no evidence of thrombosis in association with heparin-induced thrombocytopenia, thrombosis can follow after some days [ ]. Because of cross-reactivity, low molecular weight heparin should not be used when heparin has been withdrawn because of heparin-induced thrombocytopenia; nor should warfarin be used, because of the risk of venous gangrene, at least until the thrombocytopenia has resolved. Patients with life-threatening or limb-threatening thrombosis can be treated with thrombolytic drugs. Current views are that two antithrombotic drugs should be used, for example danaparoid plus lepirudin [ ].

Alternative anticoagulants have included danaparoid, fondaparinux, and sulodexide [ ], and direct thrombin inhibitors such as argatroban, lepirudin, and bivalirudin. Drotrecogin alfa (activated) has been used in the treatment of heparin-induced thrombocytopenia [ ].

Lepirudin has been used in patients with heparin-induced thrombocytopenia in a prospective study in 205 patients with 120 historical controls (HAT-3) and in a combined analysis of all HAT study data [ ]. Patients with laboratory-confirmed thrombocytopenia were treated with lepirudin in three different aPTT-adjusted dose regimens and during cardiopulmonary bypass. Mean lepirudin maintenance doses were 0.07–0.11 mg/kg/hour. End points were new thromboembolic complications, limb amputations, and death and major bleeding. The combined end point occurred in 43 (21%) of those treated with lepirudin; 30 died, 10 underwent limb amputation, and 11 had new thromboembolic complications. There was major bleeding in 40 patients, seven during cardiopulmonary bypass. Combining all the prospective HAT trials (n = 403), after the start of lepirudin treatment, the combined end point occurred in 82 patients (20%), with 47 deaths, 22 limb amputations, 30 new thromboembolic complications, and 71 episodes of major bleeding. Compared with the historical controls, the combined end point after the start of treatment was significantly reduced (30% versus 52%), primarily because of a reduction in new episodes of thrombosis (12% versus 32%). Major bleeding was more frequent in the lepirudin-treated patients (29% versus 9.1%). Thus, the rate of new thromboembolic complications in patients with heparin-induced thrombocytopenia is low after lepirudin treatment. The rate of major bleeding of 18% might be reduced by reducing the starting dose to 0.1 mg/kg/hour.

Argatroban has been used in 13 patients who developed heparin-induced thrombocytopenia after exposure to heparin 10–13 000 U from an intravascular catheter or filter flush, with a mean exposure of 8 days [ ]. They were compared with 10 historical controls who had received no direct thrombin inhibitors. The platelet count recovered to a mean of 207 × 10 ⁹ /l (n = 12) after 5.5 days of argatroban therapy and to a mean of 127 × 10 ⁹ /l (n = 8) 5 days after baseline in the control group. A composite end point of death, amputation, or new thrombosis within 37 days occurred in five argatroban-treated patients and four controls. Death was the most common untoward outcome (about 30% in each group). No argatroban-treated patient and two control patients had new episodes of thrombosis. Major bleeding was comparable.

Diagnosis Laboratory diagnosis of heparin-induced thrombocytopenia can be made either using functional tests (demonstration of platelet activation of normal donor platelets in vitro by the patient’s serum in the presence of heparin) or by screening for antibodies [ , ]. The duration of the antibody response can vary from weeks to months up to 1 year. The two types of tests are complementary; both should be used when the reported results of either are inconsistent with the clinical problem.

Susceptibility factors The risk of thrombocytopenia is increased in patients with a history of previous heparin therapy [ ]. Thrombocytopenia and/or thromboembolic complications can occur sooner in patients with a history of previous exposure to heparin, suggesting an anamnestic response [ , ].

The results of some prospective studies, including mainly transient benign thrombocytopenia (type I heparin-induced thrombocytopenia), have suggested that thrombocytopenia is more common in patients who have received the bovine lung type of heparin than in those who have received the porcine intestinal mucosa type [ ]. Type II thrombocytopenia is certainly more common in patients treated with standard heparin than in those treated with low molecular weight heparin [ ], but there is usually cross-reactivity between standard heparin and low molecular weight heparin.

Heparin-coated catheters can sustain the thrombocytopenia in patients with heparin-associated antiplatelet antibodies [ , ] and therefore have to be removed from such patients.

There is less published experience with low-molecular-weight heparins in children than in adults, but the low frequency of significant bleeding appears to be similar. A child who received therapeutic doses of a low-molecular-weight heparin for a deep vein thrombosis spontaneously developed an intramural hemorrhage in the small bowel, leading to infarction, which required partial bowel resection [ ].

Burns The incidence and complications of HIT have been studied in 625 patients with burns, of whom 43 (6.9%) underwent testing for HIT, 10 being positive; thus, the incidence among all heparinized patients was 1.6% [ ]. Thrombotic complications of HIT included arterial thrombosis requiring limb amputation (n = 2), deep venous thrombosis (n = 3), and pulmonary embolism (n = 2, of whom one died).

Cardiac surgery Anti-platelet factor 4(PF4)/heparin antibodies are often found during mechanical circulatory support, but only a few patients develop heparin-induced thrombocytopenia. In 113 patients three types of sera were identified: platelet-activating anti-PF4/heparin antibodies (n = 10), non-platelet-activating anti-PF4/heparin antibodies (n = 53), and anti-PF4/heparin antibody negative (n = 50) [ ]. The patients with platelet-activating antibodies had the highest risk of thromboembolic events, whereas those with non-platelet-activating antibodies did not differ from the antibody-negative patients. When all antibody-positive patients were further classified by an IgG-specific anti-PF4/heparin enzyme-immunoassay, the specificity for platelet-activating antibodies increased, as did the risk of HIT.

In a prospective investigation of the use of PF4/heparin antibodies to predict clinical thrombosis in 299 patients scheduled for cardiac surgery the prevalence of the antibodies was 4.3% (13 of 299) before surgery and increased more than five-fold to 22% (62 of 277) postoperatively [ ]. There were thromboembolic events in 8.8% of patients with negative antibodies and in 6.3% of patients with positive antibodies. Of the 62 patients with positive antibodies postoperatively, 22 (36%) were treated with a non-heparin anticoagulant. There was a trend toward higher rates of thromboembolic events in subjects with thrombocytopenia compared with those without (17% versus 6.7%), regardless of antibody status. Two of 8 patients with both thrombocytopenia and positive antibodies had a thromboembolic event, compared with 17 of 222 (7.7%) without clinical HIT. The authors concluded that the high prevalence of PF4/heparin antibodies after cardiac surgery and the low rate of thromboembolic complications suggested that the antibodies alone do not confer an increased risk of thrombotic complications.

Of 487 patients with thrombocytopenia (a 50% fall in platelet count or an absolute count below 100 × 10 ⁹ /l) after cardiac surgery 113 (23%) had HIT. Multivariate predictors included previous percutaneous coronary interventions (OR = 1.76), class IV NYHA heart failure (OR = 1.80), and infectious endocarditis (OR = 3.66) [ ]. Postoperative infections occurred more frequently in patients with HIT, including sepsis (17% versus 9.9%) and pneumonia (47% versus 23%). The patients with HIT also had a higher rate of renal failure requiring hemodialysis (23% versus 9.1%) and acute limb ischemia (16% versus 4.3%). Mortality at 30 days was significantly higher in those with HIT (25% versus 15%). Postoperative HIT was an independent predictor of renal failure (OR = 1.73) and thromboembolic complications (OR = 2.39).

Platelet counts have been measured in 329 patients who required ICU treatment beyond 7 days after cardiac surgery; although 70 patients (21%) developed thrombocytopenia, the overall incidence of HIT was only 1.8% (6/329; 95% CI = 0.7, 3.9%) [ ].

In a retrospective analysis of 358 consecutive patients who were given heparin during the insertion of a ventricular assist device, 28 had HIT either before (n = 15) or after (n = 13) insertion [ ].

In a review of 92 consecutive adult patients who had a ventricular assist device inserted as a bridge to cardiac transplantation, those in whom thrombocytopenia developed after heparin exposure were tested for PF4/heparin antibodies [ ]. Heparin was avoided in the 24 who were positive, but all were re-exposed to heparin during transplantation. Survival to transplantation did not differ between the groups. Compared with the controls, HIT-positive patients who were re-exposed to heparin had a greater fall in platelet counts immediately after transplantation, but there was no difference in mortality after transplantation or thromboembolism. The authors concluded that antibody-positive were not at a higher risk of thromboembolism or death after heparin re-exposure.

In a retrospective study of 3465 patients who were given postoperative heparin, 20 developed HIT within an average of 7 days [ ]. They required more platelet transfusions perioperatively than controls and thromboembolic complications occurred in 14 patients with HIT but in none of 20 matched controls. Nine patients with HIT died and all the controls survived. Mortality was related to thrombotic complications in seven patients with HIT.

In a study of the incidence of preoperative PF4/heparin antibodies and the associated risk of postoperative adverse outcomes in 1114 patients, 60 (5.4%) had positive antibodies preoperatively [ ]. These patients had longer mean postoperative lengths of stay (14 versus 9.8 days), and higher incidences of prolonged mechanical ventilation (20% versus 9.2%), acute limb ischemia (5.1% versus 0.9%), renal complications including dialysis (20% versus 11%), and gastrointestinal complications (15% versus 5.9%).

In Turkish patients undergoing cardiac surgery the incidences of heparin antibodies were 16% before surgery (n = 44), 34% on day 5 (n = 44), and 65% on day 10 (n = 115); however, platelet function (5HT release) was abnormal in only 4.4% on day 0 and 7.0% on day 10 [ ].

The prevalence of heparin-dependent platelet antibodies has been determined prospectively in 30 children after 5–10 days of postoperative exposure to heparin after cardiopulmonary bypass surgery; 15 were under 30 days old and 15 were aged between 30 days and 12 years [ ]. None had antibodies, but six had symptomatic thromboses.

HIV infection In a retrospective comparison of HIV-infected patients and uninfected patients, there was a higher incidence of HIT in the former (15/53 versus 0/106) after treatment with unfractionated heparin and/or low-molecular-weight heparin [ ].

Myeloproliferative disorders Heparin-induced thrombocytopenia is rarely reported in patients with myeloproliferative disorders; the authors of a report of three cases (two with essential thrombocythemia and one with polycythemia rubra vera) have suggested that this may be because of underdiagnosis, since these patients have high platelet counts [ ].

Vascular surgery In a prospective study of the development and function of PF4/heparin antibodies after infrainguinal bypass procedures blood samples were obtained from 79 patients before surgery and at 7, 14, and 28 days after; 67 reported previous exposure to heparin [ ]. There were PF4/heparin antibodies before surgery in six, four of whom also had a positive result on an aggregation assay. After 28 days, 22 subjects developed PF4/heparin antibodies and five of these also tested positive for platelet-activating antibodies. There were no cases of thrombocytopenia. There was early graft occlusion in three patients, but all were negative for antibodies and had normal platelet function. The authors concluded that patients who undergo vascular surgery often develop PF4/heparin antibodies, platelet-activating antibodies being detected in up to 11%, but that thrombocytopenia and vascular graft thrombosis are uncommon.

Renal disease and hemodialysis Unlike unfractionated heparin, dalteparin is mainly cleared through the kidney and can therefore accumulate if renal function is impaired, increasing the risk of hemorrhage.

• An 84-year-old woman with chronic renal insufficiency had angioplasty for a stenosis in a femorofibular bypass, developed a deep vein thrombosis, and was given dalteparin [ ]. After 4 days she developed a pronounced hematoma on her flank and her hemoglobin fell to 5.5 g/dl. Dalteparin was withdrawn and she was given protamine 2500 U and packed red blood cells. She had no further bleeding during treatment with unfractionated heparin and an oral anticoagulant.

Dalteparin should be avoided in patients with severe renal impairment or used only with close monitoring of antifactor Xa activity. As an alternative, unfractionated heparin can be used, since renal impairment does not affect its short half-life.

Two patients with chronic kidney disease had retroperitoneal hematomas requiring blood transfusion after the administration of enoxaparin [ ]. Enoxaparin should be administered with great caution in patients with chronic kidney disease, especially if antiplatelet agents or other anticoagulants are administered concomitantly.

In 419 patients on hemodialysis, 107 of whom had access thrombosis, antibodies to PF4/heparin were positive in 54 (13%); nine (2.1%) had IgG-specific antibodies [ ]. There was no relation between hemodialysis access thrombosis and PF4/heparin antibodies.

In a survey of 50 out of 81 renal units in the UK the combined population was 13 682 patients on dialysis, of whom 10 564 were on maintenance haemodialysis. The prevalence and incidence of HIT type II were 0.26 and 0.32 per 100 patients respectively. The mean age of the patients with HIT type II was 62 (range 22–86) years, 52% were women, and 92% were Caucasians. Only 17% of patients had complications of HIT.

In a review of the medical records of 122 patients with suspected heparin-induced thrombocytopenia on dialysis, 17 met the criteria of >30% thrombocytopenia, clots in the extracorporeal circulation, positive for PF4/heparin antibodies, and improvement from heparin-induced thrombocytopenia with the use of an alternative anticoagulant or another strategy for heparin-induced thrombocytopenia [ ].

Monitoring The American College of Chest Physicians has issued guidelines on the recognition, treatment, and prevention of heparin-induced thrombocytopenia [ ]. The key recommendations include the following:

• for patients in whom the clinician considers the risk to be over 1.0%, the platelet count should be monitored during heparin therapy;

• for those who are receiving heparin or have received heparin within the previous 2 weeks, HIT should be investigated if the platelet count falls by at least 50% and/or a thrombotic event occurs between days 5 and 14 inclusive after the start of heparin therapy, even if the patient is no longer receiving heparin when the thrombosis or thrombocytopenia occurs;

• for those with strongly suspected or confirmed HIT, whether or not complicated by thrombosis, an alternative non-heparin anticoagulant should be used;

• for those with strongly suspected or confirmed HIT, a coumarin should not be used until after the platelet count has substantially recovered (usually to at least 150 × 10 ⁹ /l); and when it is used it should be started in a low maintenance dose (maximum 5 mg of warfarin or 6 mg of phenprocoumon); and the non-heparin anticoagulant should be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between non-heparin anticoagulation and coumarin therapy;

• for those who are taking a coumarin when HIT is diagnosed, vitamin K 10 mg orally or 5–10 mg intravenously should be given.

In view of the severity of the type II syndrome, it has been recommended that heparin therapy be monitored by twice-weekly platelet counts [ ].

Eosinophilia . Eosinophilia has rarely been attributed to heparin, with positive rechallenge [ , ].

Skin necrosis

Heparin-induced skin necrosis was first described in 1973 [ ] and was later observed in patients with the thrombohemorrhagic syndrome [ , ]. The skin pathology develops 6–9 days after the start of subcutaneous heparin treatment and usually develops at the site of subcutaneous injection. However, it can also occur at sites distant from the site of injection [ ] or after intravenous therapy [ ]. Vasculitis is likely to be present, perhaps with fever [ ]. There is an increased risk of thrombocytopenia and thrombotic complications in patients who have had previous heparin-associated skin necrosis episodes [ ].

Skin necrosis has been reported in patients receiving tinzaparin [ ], enoxaparin [ ], and unfractionated heparin [ ].

• A 76-year-old man with polycythemia vera, hypertension, diabetes mellitus, hyperuricemia, atrial fibrillation, and chronic bronchitis, taking hydroxycarbamide (hydroxyurea), digoxin, allopurinol, and enalapril, was given prophylactic subcutaneous enoxaparin 60 mg bd [ ]. After 5 days he developed two symmetrical erythematous patches, 5 cm in diameter, on the abdominal wall at injection sites. The lesions enlarged over 24 hours and formed purplish-blue necrotic plaques 15 × 5 cm. The hemoglobin was 7.4 g/dl, the white blood cell count, 29 × 10 ⁹ /l, and the platelet count 1025 × 10 ⁹ /l; there was no significant change in the platelet count throughout the admission. The prothrombin time ratio was 1.17 and the thromboplastin time ratio 1.36. Protein C was normal but protein S was reduced to 56% (reference range 71–142%), with a low free protein S concentration (63%; reference range 72–139%) and normal total protein S (protein S deficiency type III). There were no IgG antiphospholipid antibodies, but IgM was raised. Heparin–platelet factor 4 (PF4) antibodies were also demonstrated. A skin biopsy showed multiple fibrin thrombi in the dermal microvasculature with ischemic necrosis of the overlying epidermis. Enoxaparin was withdrawn, the lesions were treated locally, and there was complete healing after about 1 month.

• A 69-year-old woman with severe bronchopneumonia was given subcutaneous prophylactic unfractionated sodium heparin (5000 IU bd) [ ]. By day 7 she had developed blistering skin lesions with central necrosis and surrounding erythema at the heparin injection sites. The platelet count was stable at 275 × 10 ⁹ /l (range 196–338). There was a circulating IgG antibody against heparin-platelet factor 4 and anticardiolipin IgG antibodies. A skin biopsy showed extensive focal epidermal necrosis with marked neutrophil infiltration and extensive fibrin deposition within the small vessels of the dermis. All the lesions resolved within 5 day of withdrawal of heparin.

• A 71-year-old white woman developed painful diffuse skin lesions, most probably related to enoxaparin [ ]. Other causes of skin necrosis, including heparin-induced thrombocytopenia, disseminated intravascular coagulation, protein C and protein S deficiencies, antiphospholipid antibodies, and vitamin K deficiency, were thought to be less likely.

Concomitant thrombophilia in the last patient may have aggravated the problem.

The association of heparin-induced skin necrosis with antibodies directed against heparin–PF4 is well-established, but the participation of other procoagulant factors has received little attention. The observation of heparin-induced skin necrosis should motivate a systematic search for the presence of anti-PF4 antibodies, but also for additional genetic or acquired procoagulant factors. Heparin-induced skin necrosis may be a marker of an increased risk of systemic arterial or venous thromboembolism.

Various physiopathological mechanisms have been suggested [ ], particularly heparin-induced thrombocytopenia, vasculitis caused by a type III hypersensitivity reaction, local trauma at the site of injection, and poor vascularization of adipose tissue resulting in reduced absorption of heparin, as seen in diabetic lipodystrophy. This form of skin necrosis must be distinguished from vasospastic skin necrosis and from skin necrosis induced by cholesterol embolization. Ergotism will be a differential diagnosis in patients who are receiving prophylaxis with the combination of low dose heparin and dihydroergotamine [ ]. In evaluating any necrotic skin reaction, one must always consider its infectious origin (particularly Escherichia coli or Pseudomonas ) related to unsterile injections [ ].

Several patients with heparin-induced skin necrosis were positive for HIT-IgG using the platelet ¹⁴ C-serotonin release assay, even though they did not develop thrombocytopenia [ ]. Skin necrosis has been particularly reported in patients receiving standard heparin but also occasionally with low molecular weight heparins, such as dalteparin [ ] or enoxaparin [ ].

The clinical and histological pictures of heparin-induced skin necrosis are similar to those found in so-called “coumarin necrosis.” Laboratory examinations show inflammatory changes, with anemia, leukocytosis, eosinophilia, a raised erythrocyte sedimentation rate, and a positive capillary fragility test. The vasculitis can lead to organ involvement, such as glomerulonephritis [ ].

Skin necrosis due to low-molecular-weight heparin has been reviewed in a systematic review of 20 articles (21 cases) in which skin necrosis occurred locally and distant from the injection site [ ]. Heparin-induced antibodies were common (positive in 9/11 cases, negative in 2/11). However, severe thrombocytopenia (platelet count below 100 × 10 ⁹ /l) occurred in only four cases, while the platelet count was normal in half of the cases. Recovery after withdrawal was usually benign, but two patients needed reconstructive surgery. The authors concluded that skin necrosis due to low-molecular-weight heparin can occur as part of heparin-induced thrombocytopenia, but that there can be other mechanisms, including allergic reactions and local trauma. When heparin-induced thrombocytopenia is excluded it is safe to switch to unfractionated heparin; otherwise, drugs such as hirudin or fondaparinux should be preferred.

As variation in the molecular weights of different heparin formulations has repeatedly been implicated in determining the frequency of sensitization, it has been suggested that the pentasaccharide fondaparinux may provide a practicable and safe alternative, because of its low molecular weight [ ]. Patients with cutaneous reactions after subcutaneous anticoagulant treatment (n = 12) underwent a series of in vivo skin allergy and challenge tests with unfractionated heparin, low-molecular-weight heparins (certoparin, dalteparin, enoxaparin, nadroparin, and tinzaparin), danaparoid, and fondaparinux. There was a high degree of cross-reactivity among heparins and heparinoids. In contrast, there was rarely cross-sensitization with fondaparinux. Molecular weight was a key determinant of sensitization to heparins and other oligosaccharides.

Heparin-induced skin necrosis can be associated with high morbidity and occasional mortality. Heparin should be withdrawn when it occurs. The risk of recurrence if heparin is given again later is not known [ ].

Fat necrosis

Subcutaneous fat necrosis has been attributed to heparin [ ].

• A 91-year-old woman with diabetes, hypertension, and unstable angina was given subcutaneous enoxaparin. After 5 days she developed extensive induration of the skin and subcutaneous fat of the upper part of the left breast and bruising of the overlying skin. There were a few patches of ecchymosis were over other parts of her body, but none at injection sites on the abdomen. Coagulation screen and platelet count were normal. Mammography showed asymmetrical nodular densities over the upper inner quadrant of the left breast and ultrasound of the area was consistent with fat necrosis.