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Heparin is the most commonly used anticoagulant in the hospitalized
patients. Heparin induced thrombocytopenia (HIT) is the most feared adverse
effect of heparin therapy. Unfractionated heparin (UFH) causes 10 fold higher
incidence of HIT compared to the low molecular weight heparin (LMWH). HIT is
divided into two types, type1 or heparin associated thrombocytopenia (HAT)
which is benign and self-limiting and type 2 heparin induced thrombocytopenia
commonly called HIT is an immunologically mediated and potentially limb and life
threatening entity. HIT frequently manifests as thrombocytopenia, thrombosis
and limb gangrene. A combination of clinical probability score and immunoassay
are used for the diagnosis of HIT.
The management of HIT patients is stopping all forms of heparin and using
alternative anticoagulants either direct thrombin inhibitors or selective anti
Xa agents. Newer oral anticoagulants are increasingly used in the treatment of
HIT, but need more evidence for their routine use in these patients. HIT can be
prevented up to some extent by minimizing the use of UFH.
Keywords: Direct thrombin
inhibitors, Heparin induced thrombocytopenia, Low molecular weight heparin,
Unfractionated heparin, Thrombocytopenia, Thrombosis
INTRODUCTION
Heparin (unfractionated Heparin/UFH) has
remained an anticoagulant of choice, right from the time of its discovery more
than 100 years ago. Heparin use in medical practice is increasing due to the
increase in the number of vascular interventions and aging population. It is
estimated that up to 30% of in-hospital patients need some form of heparin
during their hospital stay [1]. Although a number of oral and parenteral newer
anticoagulants are available in the market, heparin has an advantage of rapid
onset of action, easy to titrate and monitor. Due to this pharmacological
profile heparin seems to be remaining as anticoagulation of choice.
Thrombocytopenia is one of the common
abnormalities in critically ill patients. It is caused by different conditions
from sepsis to intravascular devices and it is closely related to the outcome
of these intensive therapy unit patients [2]. Heparin Induced Thrombocytopenia
(HIT) is most feared complication of heparin use. HIT is a procoagulant,
clinicoimunological condition with thrombocytopenia in patients on heparin
therapy, decrease in platelet count by 50% or to less than 100 × 103/L,
from 5 to 14 days of therapy. HIT is associated with high morbidity, mortality
and longer hospital stay of the suffering patients [3].
EPIDEMIOLOGY
Incidence of HIT (heparin Induced Thrombocytopenia) varies with type and duration of heparin used, around tenfold higher with UFH than with LMWH (Low Molecular weight Heparin) in surgical patients treated with prophylactic doses [4]. When compared between bovine and porcine heparin, Incidence is significantly low with porcine heparin [5]. HIT is more common in surgical patients compared with medical patients, highest incidence is in cardiovascular, orthopedic surgical patients and it is lowest (<1%) in obstetric patients [5]. HIT is more frequent in tissue derivation of heparin, bovine>porcine, intravenous route of administration>subcutaneous and more frequent in females than in males [6].
CLASSIFICATION, TERMINOLOGIES
AND CLINICAL VARIANTS OF HIT
HIT is divided into the following categories depending if clinical and
immunological variations:
1. HIT
type I (heparin associated Thrombocytopenia or HAT) is mild, transient and
non-immunological. Typically occurs within first 3 days heparin therapy and
platelet count returns to normal with continued heparin administration. The
mechanism appears to be the destruction of the positively charged platelets by
negatively charged heparin molecules. It’s a benign condition without any
thrombosis and platelet count improves with continuation of UFH and its
derivatives (Table 1).
2. HIT
type II (Heparin-induced thrombocytopenia and thrombosis/HITT) is a clinically
relevant entity, limb and life threatening emergency. The immune reaction
between heparin and platelet factor4 causes thrombocytopenia and vascular
thrombosis. It’s a profound prothrombotic condition, requires not only the
stopping of heparin and its derivatives but starting of alternative
anticoagulation therapy (Table 1).
3. Subclinical
HIT or sub-acute is where a patient has recovered from an HIT with improved
platelet levels but has persistent antibodies. The Remote HIT refers to
platelet count recovery and negative heparin-PF4 antibodies. These individuals
with sub-acute or remote HIT are at higher risk of HIT recurrence with feature
exposer to heparin.
4. Delayed-onset
HIT is the occurrence of thrombocytopenia and/or thrombosis 5 or more days
after stopping heparin and it may be related to the higher antibodies levels.
5. Refractory
or persistent HIT is a persistent thrombocytopenia and/or thrombosis that may
last for weeks after heparin stopped.
6. Spontaneous HIT: It occurs in the absence of recent heparin exposure; affected patients have a preceding infection or have undergone a major surgical procedure [7].
RISK FACTORS
Approximately 5% of the patients on heparin therapy for longer than 4
days develop HIT. Following factors increase the risk of developing HIT:
1. Surgical intervention
particularly patients undergoing cardiac and orthopedic surgeries [8].
2. Unfractionated heparin versus Low
Molecular Weight heparin (LMWH), although patients can have HIT
whether the heparin exposure was to UFH or LMWH, HIT occurs more commonly after
exposure to UFH compared to the LMWH [9].
3. Heparin route and dosage,
patients on therapeutic doses of heparin have a greater incidence of HIT than
prophylactic doses. In a review of more than 20,000 patients exposed to UFH,
HIT occurrence was 0.76% in therapeutic intravenous heparin where as it was
less than 0.1% in patients on prophylactic subcutaneous heparin [10]. It is
reminded that there is no dose of heparin that is too low to cause HIT and HIT
can even occur without exposure to heparin.
4. Gender, females are
twice at the risk of HIT compared with males. It is interesting to know that
the female predominance of HIT was restricted to those receiving unfractionated
heparin [11].
5. Age, the elderly patients are at higher a risk for HIT, It is rare in patients <40 years. It is also noted that the incidence of HIT is very low in the postpartum period [11].
PATHOPHYSIOLOGY
The hypercoagulable state in HIT is multifactorial. There is platelet activation with the formation of procoagulant PF4/heparin/immunoglobulin complex, increase in thrombin generation, activation of intrinsic tissue factor and neutralization of anticoagulant effect of heparin [12]. Antibodies are form within 4 days to the PF4 (Platelet factor4) and the heparin (Figure 1). Thus the antigen is PF4/heparin complex. PF4 is a positively charged protein stored in platelet α-granules and released in high quantities when platelet are activated, the released PF4 binds to negatively charged heparin on nearby endothelial cells, displaces bound anti-thrombin, thus releasing abundant of thrombin into the circulation and creating a prothrombotic state. Heparin infusions displace released PF4 from vascular or other cell-binding sites into the circulation allowing for formation of immunogenic PF4/heparin complexes (Figure 1). The immune response to PF4/heparin occurs far more frequently than clinical manifestations of thrombocytopenia or thrombosis. The antibody formation differs in general medical and surgical patients treated with heparin and it is 8 to 17%, lower for LMWH and fondaparinux (2 to 8%) and it reaches around 50% in patients undergoing cardiac surgery. PF4 binds effectively to bacterial walls of gram +ve and –ve bacteria, in combination with platelet activation subsequent PF4 release, it may cause enough priming stimulus for an immune response for subsequent heparin exposure. PF4/heparin complexes cause dysregulating innate immunity, binding of PF4/heparin complexes to B cells, mediated by C3 activation, this ultimately enhancing its immunogenicity by 1000 to 10,000-fold. It contributes to subsequent antibody production [13].
The Venous thrombosis is common in HIT patients and the risk factors
are IgG isotype, high activation of the platelets and high antibody levels
[14]. The HIT thrombus is also called white thrombus, as it is characterized by
massive, rapid clumping of platelets and fibrin, in contrast to other
etiological clot, which is red colored as it contains a lot of red blood cells
[15].
CLINICAL MANIFESTATIONS
Any patient on heparin having the following manifestations should raise
high index of suspicion HIT in patients receiving heparin for 4 to 10 days, new
thrombocytopenia, venous or arterial thrombosis, necrotic skin lesions around
heparin injection sites and acute systemic reactions after intravenous heparin
therapy.
Thrombocytopenia
Thrombocytopenia precedes thrombosis in HIT patients, It is the most
common manifestation of HIT, occurs in up to 90% of patients. Common to find
platelet count of around 60,000/uL but it can go down as low as 20,000/uL [16].
Timing of thrombocytopenia: Onset of thrombocytopenia typically occurs
following 5 to 8 days of heparin therapy. In 30% patients, early onset of
Thrombosis
It occurs in 50% patients with HIT. It is a life and limb threatening
complication. Venous thromboembolism is more frequent and common to find at the
site of insertion of central venous catheter [19]. Thrombocytopenia severity
indicates the thrombotic risk, the marked thrombocytopenia having more than 8
fold increased risk of thrombosis compared to patients having less than 30%
decrease in platelet count [20].
Limb gangrene
Venous limb gangrene was more common than arterial thrombosis and
occurs in 5% of HIT patients. It is suggested that acquired protein C
deficiency cusses the venous gangrene in these patients [21].
Bleeding
It is reported in 6% of HIT patients and it is not clear whether the
bleeding occurs due to thrombocytopenia or non-heparin anticoagulation therapy
[22].
Organ ischemia or infarction
Thrombosis can cause stroke, myocardial infarction, acute limb ischemia from peripheral arterial occlusion, or organ infarction [23]. The unusual thrombotic complications including adrenal hemorrhage due to adrenal vein thrombosis and transient global amnesia because of brain ischemia are reported [24].
Anaphylaxis
Acute systemic anaphylactic reactions can be fatal; thrombocytopenia
may be absent in spite of clinical as well as laboratory evidence of HIT [25].
Diagnosis
HIT is diagnosed by combination of clinical score system and laboratory
tests. It is of vital importance to avoid false positive diagnosis of HIT,
hence it is reported that patients with initial clinical criteria showing
moderate to high probability of HIT should further be evaluated by laboratory
tests [26].
Clinical score system
The clinical criteria have been developed to help clinicians in
diagnosis of HIT. The commonly used clinical scoring system is 4T’s score, HIT
expert probability score and Lillo-Le Louët model score.
4T’s score
This scoring system is developed by Warkentin, it is the simple and
most commonly used for the probability of
calculation, due
to operator inexperience, resulted in misclassification in ∼2% of cases [28]
Patients with intermediate and high 4T score should have further laboratory
test to confirm the diagnosis of HIT [12].
HIT expert probability score
It is described by Cuker, uses eight clinical features and an expert
opinion for diagnosis of HIT. It demonstrated improved correlation between the
serologic HIT testing and inter-observer agreement; it required a prospective
validation [29].
Lillo-Le Louët model score
This scoring is used only for the post-cardiopulmonary bypass patients,
scoring points are based on timing, duration of thrombocytopenia and the
duration of cardiopulmonary bypass [30].
Laboratory tests
For the diagnosis of HIT it is necessary to have presence of
anti-PF4/heparin antibodies in patient’s serum, or activation of platelets by
either functional or immunoassay.
Functional or platelet
activation assays
The commonly used are 14C-SRA, platelet aggregation, and recently
flow-based platelet activation assays detect antibodies capable of binding and
cross-linking platelet. These functional assays are specific but not sensitive.
The Specificity is more than 95% with PPVs of 89% to 100% and a low sensitivity
of 56% to 100%. These assays are technically difficult to perform and available
only in few medical centers [31].
Immunoassay
In contrast the immunoassays measure the presence of anti-PF4/heparin
antibodies using enzyme-linked immunosorbent assay, particle gel or
immune-turbid metric. The advantages of immunoassays are technically simple and
highly sensitive (>99%), but lower specificity of 30 to 70% in the diagnosis
of HIT [32].
DIFFERENTIAL DIAGNOSIS
HIT should be differentiated from disseminated intravascular
coagulation (DIC), heparin toxicity and hyper-responsive thrombocytopenia. It
is important to differentiate these clinical entities from HIT as their
management is different from that of HIT. DIC is the activation of
intravascular coagulation leading to thrombocytopenia, bleeding occurs in
diseases ranging from sepsis to trauma and obstetrics. It is differentiated
from HIT by prolonged coagulation parameters with elevated fibrinogen
degradation products [33].
In acute heparin toxicity there is overdose of heparin, it can be
fatal. Commonly manifested as wound bleeding, oozing mucosal membrane and in
more severe case intraventricular hemorrhage. It is differentiated from HIT by
abnormal activated prothrombin time and thrombocytopenia [34]. In
hyper-responsive thrombocytopenia platelets are actively involved and consumed,
seen in acute bronchial asthma patients leading to bronchoconstriction with
airway inflammation and thrombocytopenia. It can be differentiated from HIT by
the signs and symptoms of primary disease causing hyperactive response [35].
COMPLICATIONS
The more frequently seen complications in HIT patients are
venous/arterial thrombosis, skin lesions and acute platelet activation
syndrome.
Venous thromboembolic complications are four times common than arterial
thrombosis. The thrombosis mainly occurs in the larger vein, bilateral deep
venous thrombosis and pulmonary embolism. Rarely can it cause thrombotic
stroke, adrenal hemorrhagic infarction or cerebral venous sinus thrombosis.
Arterial thrombosis can cause myocardial or brain infarction [36]. Skin
necrosis or/and erythematous plaques occur at the site of heparin injections.
Acute platelet activation syndrome in HIT patients will manifest by an acute
inflammatory response with fever and chills. In spite of the severe
thrombocytopenia the hemorrhagic complications occurs in around 6% HIT patients
[37].
Management
To simplify we will discuss the HIT management in following
subheadings:
Immediate interventions: These patients need immediate treatment for
reduction of the risk of life-threatening thrombosis. The treatment should be
started based on a strong clinical suspicion of HIT and on an intermediate or
high probability 4 T’s score while the laboratory test results are awaited.
These initial interventions are discontinuation of all heparin, reversal of
warfarin and initiation of a non-heparin anticoagulant. Two major goals of
these interventions are to halt platelet activation as early as possible and to
provide therapeutic anticoagulation with a non-heparin-anticoagulant to reduce
the risk of thrombosis.
Heparin alternative
HIT patients stopping heparin alone will not be sufficient as these
patients remain at risk for subsequent thrombosis. Anticoagulation is required
in HIT patients having essential procedures or emergencies, acute coronary
syndrome and thromboembolic phenomenon. Alternative anticoagulant should be
free from generating HIT antibodies or cross-react with anti-heparin-platelet
factor 4 antibodies. Vital aspects of selection of these alternative
anticoagulant agents are familiarity, safety with efficacy, patient’s organ
functions, clearance of agents, the urgency of anticoagulation, need for
reversal and the monitoring techniques [38].
Heparin alternatives available are direct thrombin inhibitors, which
directly inhibit thrombin generation (argatroban, bivalirudin), selective
factor X inhibitors (danaparoid, Fondaparinux) and the vitamin K antagonist
warfarin or direct oral anticoagulants (DOACs) apixaban, edoxaban, rivaroxaban
or dabigatran.
TREATMENT
In HIT patients the higher risk of thrombosis is from the time of
diagnosis of HIT to the starting of alternative anticoagulation agents. Hence
the management of HIT patient should be started without delay and waiting for
the results of confirmatory laboratory tests [39]. The management of HIT
patients is summarized by 6 “A”s [40].
1) Avoid
and stop all heparin (any form, any route, heparin flush or heparinized
catheters).
2) Administer
direct thrombin inhibitors (alternative anticoagulation).
3) Anti-PF4/heparin
antibody test for confirmation of diagnosis.
4) Avoid
platelet transfusion.
5) Await
platelet recovery.
6) Assess
lower extremity thrombosis.
LMWHs (Low molecular weight heparin) are contraindicated in patients
with HIT due to their cross-reaction with heparin antibodies, and in acute
phase of HIT warfarin is contraindicated as it paradoxically worsens the
thrombosis due to a drastic decrease in protein C levels [41]. Warfarin can be
used only after the alternative anticoagulation and platelet count improves to
more than 150,000/uL.
Choice of anticoagulation
Urgency of anticoagulation: In patients with an acute thrombosis, a
parenteral agent is required to achieve the therapeutic anticoagulation as
early as possible, by argatroban, bivalirudin, danaparoid or a DOAC (direct
oral anticoagulant).
Urgent reversal possibilities: For patients requiring invasive procedure or
those with higher risk for bleeding, we have to use an anticoagulant agent
which can be reversed quickly. In these patients either argatroban or
bivalirudin are the choice as they have a short half-lives and effects will be
vanished within 1 h following discontinuation if they have no organ
dysfunction.
Renal impairment/failure: In these patients commonly argatroban is
used in the therapeutic doses, when platelet counts are stabilized, warfarin
can be used, with close monitoring. Rivaroxaban and apixaban can be used in
patients with end-stage renal failure and atrial fibrillation.
Hepatic impairment/failure: In these patients danaparoid, fondaparinux
or bivalirudin in therapeutic doses are the drug of choice. The DOACs can be
used in mild hepatic insufficiency and not advisable in moderate to severe
liver disease.
Both renal and hepatic
insufficiency: In this group
of patients argatroban or bivalirudin is used at reduced dosages. When patient
is stably anticoagulated can be shifted to warfarin. Apixaban is increasingly
used in patients with renal impairments.
Other considerations: The local availability, institutional or/and
clinician familiarity/preference and cost should be considered while selecting
the anticoagulation in HIT patients. Patients cannot be on an intravenous
agent, fondaparinux or one of the DOACs may be used and patients who cannot
take an oral agent, fondaparinux or direct thrombin inhibitors are the
anticoagulation of choice. These patients with HIT require therapeutic rather
than prophylactic dosing, with the exception of patients with combined renal and
hepatic impairment.
Duration of anticoagulation
therapy: It’s based on
concurrence of thrombosis. The American and British guidelines recommend
therapeutic dose anticoagulation for 4 weeks in patients with isolated HIT and
up to 3 months for HIT patients with thrombosis [42,43].
PHARMACOLOGY OF ALTERNATIVE
ANTICOAGULATION
DTI (Direct Thrombin
Inhibitors)
DTI are the medications of choice in patients with HIT. These agents
neither interact with heparin-dependent antibodies nor need an anti-thrombin as
a cofactor. DTI have a predictable anticoagulant effect. They rapidly stop the
thrombin storm and prevent new thrombus formation.
The DTI are argatroban, lepirudin, desirudin, bivalirudin, melagatran,
and ximelagatran. Last 2 medications are no more available in the market. As
per the structural configuration DTI are divided into 2 groups.
Divalent DTI: lepirudin and desirudin are 65-amino acid,
polypeptides; the amino terminal binds to the catalytic site whereas carboxyl
terminal irreversibly binds to the exosite of thrombin. Bivalirudin is a
20-amino acid derivative of hirudin, the peptide bond slowly cleaved from the
catalytic site on thrombin; hence it is a reversible inhibitor of thrombin with
shorter half-life. Lepirudin and desirudin are given by intravenous and
subcutaneous routes, and half-life is 60 and 120 min, respectively, both of
them are excreted through the renal system, hence requires dose adjustment in
renal insufficiency patients. The initial loading dose is 0.4 mg/kg, then 0.15
mg/kg/h. Bivalirudin is given intravenously, largely cleared by peptidase but
20% is excreted through the kidneys, and needs dose adjustment in patients with
renal impairment [44]. Patients receiving lepirudin should be monitored 4 h
after the initiation of therapy and the target activated partial thromboplastin
time (aPTT) should be 1.5-2.5 times , Desirudin does not need monitoring except
in patients with renal impairment. Bivalirudin should be monitored by activated
clotting time (ACT) in patients with renal insufficiency or increased risk of
bleeding.
Monovalent DTI: Argatroban is l-arginine-based molecule,
shorter activity and reversibly binds to thrombin. It has a half-life of 50 min
and mainly excreted through the liver and requires dose adjustment in patients
with hepatic impairment. It is given by intravenous route and monitored with
aPTT levels [45]. Ximelagatran is a prodrug, given by the oral route and
metabolized in the liver to active form, whereas melagatran has a predictable
anticoagulation effect and longer half-life. Its clearance is not affected by
liver impairment or moderate renal insufficiency and hence there is no need to
monitor the levels unless the renal impairment is severe [46]. The major
concern with DTI is the risk of bleeding and it is higher with lepirudin and
desirudin when compared with argatroban and no specific antidote is available
for DTI. PCC (Prothrombin complex concentrate) is increasingly used in
reversing the DTI anticoagulation effect.
Danaparoid is a heparinoid derivative, interacts with
anti-thrombin III to inhibit factor Xa. It is not available in USA, but used in
few other countries. It has cross-reactivity with antibodies in 15% of the
patients [47]. It’s given subcutaneously or intravenously. Disadvantages are,
it needs anti Xa level monitoring, has a long half-life (around 25 h), has
renal excretion and absence of a reversal agent.
Fondaparinux is a synthetic pentasaccharide, it
selectively inhibits factor Xa. The therapeutic dose of fondaparinux ranges
from 5 to 10 mg/day, subcutaneously, although the levels can be measured, not
required routinely. The disadvantages includes long half-life of around 17
hours, renal elimination and the lack of an antidote [48].
(DOACs) Direct oral anticoagulants are the oral anticoagulants that directly
act on thrombin that is dabigatran or factor Xa inhibition, these are apixaban,
edoxaban, rivaroxaban, they are not stimulating HIT antibodies. There is more
experience was with rivaroxaban use in HIT patients. DOAC can be given as initial therapy or can
be preceded by a parenteral agent in these patients.
SPECIAL SCENARIOS WHERE HEPARIN
IS NEEDED BUT CANNOT BE USED DUE TO HIT
If patients on hemodialysis, percutaneous coronary Intervention (PCI), cardiopulmonary Bypass (CPB), unstable angina, thromboembolism, indwelling devices, valve replacement or intra-aortic balloon pump, develop HIT, they will require alternative anticoagulation therapy.
Hemodialysis
HIT antibodies are positive in up to 17% of the patients on
hemodialysis with a significantly higher mortality. The manifestation of HIT in
these patients varies from acute systemic reaction to frequent clotting in the
extracorporeal circuit or increase in the number of failed arteriovenous
fistula. When HIT is suspected in these patients: all forms of heparin should
be stopped and start DTI or danaparoid or regional citrate anticoagulation.
Argatroban has advantage in these patients as no dose adjustment is required;
the recommended dose is an initial bolus of 250 mcg/kg at the start of dialysis
then continuous infusion of 2 mcg/kg/min until 1 h before the end of dialysis
session. Only bolus dose of lepirudin recommended at the beginning of dialysis
session. This DTI has to be monitored with aPTT [49].
Percutaneous coronary
interventions and cardiopulmonary bypass
Hypercoagulability in HIT patients in combination with endovascular
disruptions in PCI and CPB increases the risk of thrombosis. Argatroban, bivalirudin
and danaparoid are the frequently used in PCI. If it is possible CPB surgeries
should be postponed till PF4-heparin antibodies are negative, if cannot be
delayed the bivalirudin, lepirudin, argatroban or danaparoid can be used.
Unstable coronary syndrome
These patients may need full anticoagulation for longer period,
initially the intravenous argatroban is used successfully in HIT patients with
unstable coronary syndrome and later on they can be managed with DOACs [50].
Multiple organ failure and HIT
Critically ill HIT patients with multiple organ dysfunction/failure and
may have hepatic/renal impairment or failures, the dose of DTI must be adjusted
with monitoring of the coagulation parameters and organ functions. The lack of
antidote will put critical patients at the risk of potential risk of bleeding.
Bivalirudin demonstrated better safety as it is cleared predominantly by the
enzymatic cleavage.
Pregnancy and HIT
Fortunately HIT is rare in pregnancy. When a HIT patient becomes
pregnant may require thromboprophylaxis and/or treatment for thrombosis. It is
of extreme important to use an anticoagulant that causes the minimal risk to
the developing fetus. Danaparoid, subcutaneous lepirudin and Fondaparinux are
commonly used; there is limited literature available about their effects on
fetus and newborn [51].
MORBIDITY AND MORTALITY
Early diagnosis and earlier management of HIT can reduce the morbidity
and mortality, 20% of HIT patients with thrombosis need amputation [52]. In HIT
patients treated with DTI, mortality decreases to 16% and the incidence of new
thrombus decreases to 5.8% [53]. Small doses of thrombolytic agents were used
locally in HIT patients with good results in massive pulmonary embolism or
arterial thrombosis [54]. Ralph-Edward successfully managed a case of massive
pulmonary embolism in a patient with HIT by embolectomy [55]. The immune memory
in Hit patients lasts for 90 days in around 35% of patients. Immunoassay is
positive up to 1 year [56]. Platelets come to the normal range in a week of
discontinuation in approximately 65% of patients [57]. After the platelet count
recovery, patients will be at risk for thrombosis for 4 to 6 weeks because of
circulating anti-PF4/heparin antibodies. Patients who are re-exposed to the
heparin months to years after antibody disappearance do not manifest anamnestic
responses. In a small study of 17 patients with HIT who are re-exposed to
heparin for cardiac surgery, a higher proportion of patients developed
anti-PF4/heparin antibodies (65%) relative to the incidence described in the
literature (∼27% to 51%) [58].
PREVENTION
By following measures below will decrease the HIT occurrence (a)
Keeping heparin therapy for shorter duration and starting warfarin early if
expecting prolonged anticoagulation. (b) Avoiding bovine and fractional heparin
and using LMWH. (3) Stopping the use of heparin flush for central and arterial
catheters. (d) Heparin-free dialysis and not using heparin lock [59].
Sunnybrook Health Sciences Center, Toronto/Canada, implemented the “Avoid
Heparin” campaign: in this campaign they replaced the use of UFH with LMWH for
thromboprophylaxis and/or treatment, removed UFH from catheter flushes and
nursing units. By this campaign the investigators found a significant reduction
in percentage of occurrence of HIT [60,61].
CONCLUSION
For more than 100 years from the time of discovery, heparin remained
most frequently used anticoagulant in the clinical practice. Its use is
increasing as the patient population is getting older and number of vascular
surgeries is increasing day by day. Heparin has advantages of rapid, shorter
duration of Action and easy reversibility. The heparin induced thrombocytopenia
(HIT) is a known but potentially life threatening complication of heparin use,
it’s more frequent in females, young and surgical patients. HIT is diagnosed by
4T’s score in combination with laboratory test. The functional laboratory test
(platelets aggregation test) is more specific but less sensitive and not
routinely done. Immunoassay is commonly done laboratory test, it is sensitive
but not specific. Optical density will increase the specificity of
Immunoassays. Thrombocytopenia and thrombosis are common complications but the
hemorrhage is rare in HIT patients. The management of HIT is summarized by 6
“A” Avoid heparin, alternative anticoagulation, anti PF4 antibodies detection,
avoid platelet transfusions, await platelet recovery and asses for thrombosis.
HIT can be prevented by use of porcine heparin, low molecular weight heparin,
shorter duration of intravenous therapeutic heparin, avoiding heparin flush for
central venous and arterial catheters and heparin lock.
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