SQU Med J, August 2011, Vol. 11, Iss. 3, pp. 391-398, Epub. 15th Aug 11
Submitted 3rd Feb 11
Revision ReQ. 11th Apr 11, Revision recd. 18th Apr 11
Accepted 18th May 11

1Department of Haematology, Sultan Qaboos University Hospital, Muscat, Oman; 2Department of Haematology, The Adelaide & 
Meath Hospital, incorporating the National Children’s Hospital, Tallaght, Dublin, Ireland.
*Corresponding Author email: sskindi@squ.edu.om

<l^vÈÀí÷]<ìœfi<t¯¬<ª<Ì◊ËÇf÷]<Ün~j÷]<l]Å^ñ⁄<›]Ç~jâ]<|^®
VÜn~j÷]<l^À¬^ñ⁄<ƒ⁄<‡ËÖ^fÈ7]<Ÿ^€√jâ]<‡¬<si^fl÷]

l^ÈeÅ_<Ì√q]Ü⁄<ƒ⁄<l˜^u<ã∏<ÜËÜœi<



 35%
  1%  
  
1282  x  10938.4  x  109 7 – 1410.2
 
   

 6 14 4



  :مفتاح الكلمات

aBstract: Heparin is one of the most frequently used anticoagulants. It is easy to use, but can be associated 
with life-threatening side effects. One of these is heparin-induced thrombocytopenia syndrome (HITS), which 
develops in about 3–5% of patients exposed to heparin and is associated with thrombosis in 1% of cases. We report 
here the successful treatment of five patients with HITS who were treated with alternative anticoagulants namely 
danaparoid or hirudin. The median time between their exposure to heparin and onset of symptoms and or signs 
was 10.2 days (range 7–14 days). Platelet counts decreased to a mean of 38.4 x 109 /l (12–82 x 109/l). All five patients 
had evidence of thrombosis; four patients had clinical and radiological evidence of pulmonary emboli, one patient 
had confirmed deep vein thrombosis (DVT) and one patient had extensive skin necrosis of the thighs and abdomen. 
Platelet aggregation test were positive in two patients, inconclusive in one patient and negative in two patients. Two 
patients were anticoagulated with danaparoid and three with hirudin until their platelet counts returned to normal 
between 4 and 14 days (average 6 days) following the recognition of the syndrome. Our patients had significant 
morbidity, but no mortality. Immediate withdrawal of heparin is of paramount importance and introduction of 
alternative anticoagulant is necessary in the presence of thrombosis. 

Keywords: Unfractionated heparin; Low-molecular weight heparin; Heparin-induced thrombocytopenia; Hirudin; 
Danaparoid; Case report; Oman

Successful Use of Alternative Anticoagulants in 
the Management of Heparin-induced 
Thrombocytopenia with Thrombotic 

Complications
Report of 5 cases and review of literature

*Salam Alkindi,1 Owen P Smith,2 Helen Enright2

CASE REPORT



Successful Use of Alternative Anticoagulants in the Management of Heparin-induced Thrombocytopenia with  
Thrombotic Complications 

Report of 5 cases and review of literature

392 | SQU Medical Journal, August 2011, Volume 11, Issue 3

Heparin is one of the most useful drugs in the prevention and treatment of arterial and venous thromboembolic 
diseases. It is generally very well tolerated, but it can 
be associated with a number of serious side effects,  
heparin-induced thrombocytopenia syndrome 
(HITS) being one of them.1 

There are two types of HITS. Type 1 HITS 
is mild, transient, non-immune-mediated 
thrombocytopenia and occurs commonly following 
the institution of heparin. It is believed to be 
due to platelet aggregation and removal by the 
reticuloendothelial system. It is not associated with 
thrombosis, and no treatment is required; heparin 
withdrawal also may not be necessary. Type II, or 
immune-mediated HITS, on the other hand is a 
more serious condition. It is thought to be due to 
immunoglobulin (usually immunoglobulin G (IgG), 
but also IgM and IgA).1 It usually develops 5–14 
days following exposure to all types of heparin, 
including low molecular weight heparin (LMWH), 
or immediately following the second exposure to 
heparin.2 

Heparin dependent antibodies are frequently 
encountered, however thrombocytopenia/ 
thrombosis is seen only in about 3–5% of patients 
exposed to heparin, with thrombosis seen in 
about 1%. Usually this occurs 5–10 days after the 
initiation of heparin therapy.3,4,5 The incidence of 
thrombocytopenia was thought to be lower in 
LMWH as compared to unfractionated heparin 
(UFH); however, recent data suggest it is not as low 
as was initially thought.6 This may be due to the 
lesser interaction between LMWH and platelet PF4, 

which is crucial for the development of HITS.3‒5 We 
report here five cases of Type II HITS developed 
following exposure to heparin sodium salts 
including LMWH. Our aim is to highlight the need 
for vigilance in monitoring patients with recent 
exposure to heparin preparations, allowing early 
recognition of the syndrome and commencement 
of prompt and appropriate therapy.

Methods 
The medical records of our patients who were 
diagnosed as having HITS over a one year 
period were retrospectively evaluated. Once the 
diagnosis of HITS is suspected, samples are taken 
for aggregation studies. Platelet aggregation is 
performed by combining platelet-poor patient 
serum to donor platelets, and adding heparin, 
or a control solution of normal saline. Platelet 
aggregations are then measured for 15 minutes using 
a platelets aggregometer, and the test is considered 
positive when light transmission changes ≥20%. 

Case One
A 55 year-old man was admitted for total hip 
replacement and received LMWH (enoxaparin) 
prophylaxis. A week later he became breathless, 
weak, and fainted with sudden onset of apnoea; 
the electrocardiogram (ECG) monitor showed slow 
atrial fibrillation. Cardiopulmonary resuscitation 
was performed, after which emergency angiography 
showed bilateral pulmonary emboli. Preoperative 

Table 1: Summary of important demographic and haematological parameters of all five cases

Case # 1 2 3 4 5

Age (years) 55 68 42 51 74

Sex M F F M M

Platelets at admission x 109/l 201 182 225 182 139

White blood count at admissions x 109/l 7.1 12.9 7.2 6.1 7.8

Type of heparin used Enoxaparin Enoxaparin Minihep Minihep Minihep

Duration of heparin therapy (days) 9 14 11 14 7

Nadir platelets counts x 109/l 78 48 12 25 35

Therapy used Danaparoid Danaparoid Hirudin Hirudin Hirudin

Day 10 platelet count x 109/l 240 287 261 210 156

Time to normal counts (days) 9 7 4 6 9



Salam Alkindi, Owen P Smith, Helen Enright

Case Report | 393

counts showed Hb 14.1 g/dl, white blood cells (WBC) 
7.1 x 109/l, platelets 201 x 109/l. At the onset of the 
pulmonary embolism, the blood counts showed Hb 
10g/dl, WBC 20 x 109/l and platelets 82 x 109/l. His 
platelet count dropped further to 78 x 109/l. Further 
investigation showed prothrombin time (PT) 10.6 
seconds, activated partial thromboplastin time 
(APTT) 26.1 seconds, fibrinogen 2.36 g/l, D-dimers 
> 6.4 < 12.8. Testing for HIT by aggregation studies 
was negative. Treatment was commenced with 
danaparoid infusion, while the tissue plasminogen 
activator (t-PA) and LMWH were discontinued. He 
developed transient acute renal failure requiring 
dialysis due to transient hypotension. The platelet 
count returned to normal on day nine following the 
episode, when danaparoid was discontinued and he 
was commenced on warfarin. 

Case Two
A 68 year-old diabetic woman with ischaemic heart 
disease and peripheral vascular disease was admitted 
with bilateral gangrenous toes [Figure 1]. She was 
treated with heparin followed by aortoiliac stenting. 
Postoperatively she received clexane (enoxaparin) 
subcutaneous injections. Two weeks later, she 
became acutely dyspnoeic with tachycardia, melena, 
and multiple necrotic skin lesions developed at 
the site of heparin injections on her thighs and 
abdomen [Figure 1]. Investigations showed Hb 6.3 
g/dl, WBC 12.9 x 109/l, platelets 48 x 109/l. HIT 
testing by platelet aggregometry was equivocal. The 
LMWH was discontinued. She was treated with red 
cell and platelet transfusion, and her anticoagulant 
treatment was changed to danaparoid (organon) 
750 IU twice a day (BD) subcutaneously (SC) until 

her platelet count returned to normal; this occurred 
7 days following the initiation of danaparoid.

Case Three
A 42 year-old woman with menorrhagia underwent 
a total abdominal hysterectomy. Prophylaxis with 
“minihep” (low dose unfractionated sodium-
heparin: 5000 IU BD SC) was commenced the day 
before surgery. On admission the complete blood 
count (CBC) was as follows: Hb 10.9 g/dl, WBC 
7.2 x 109/l and platelets 225 x 109/l. She was on 
minihep post-operatively until she was discharged. 
Three days after the discharge, she presented with 
vaginal bleeding and right calf pain and tenderness. 
A Doppler scan confirmed deep vein thrombosis. 
Full blood counts showed Hb 10.8 g/dl WBC 5.3 
x 109/l, platelets 12 x 109/l; the coagulation screen 
was normal apart from elevated D-dimers. She was 
transfused with platelets. HIT testing by platelet 
aggregometer was negative. She was treated with 
hirudin until her platelet count returned to normal 
(on the fourth day of hirudin infusion), and was 
subsequently anticoagulated with warfarin for 6 
months.

Case Four
A 51 year-old man underwent anterior resection at 
another hospital for a colon carcinoma. He received 
unfractionated heparin (UFH, minihep) prophylaxis 
pre- and postoperatively. His CBC prior to surgery 
showed Hb 10.7 g/dl, WBC 6.1 x 109/l, platelets 
182 x 109/l. Three weeks later, he was admitted to 
our hospital with a 3-day history of gradual onset 
of dyspnoea and haemoptysis with swelling of 

Table 2: Therapeutic agents used to treat heparin-induced thrombocytopenia (HIT)

Agent Dose Grade of 
recommendation

Advantages Disadvantages

Danaparoid sodium 2000–3000 loading 
done 
150–200/hr 
maintenance dose

1B Can be used in severe 
renal failure.
Used in HIT 
prophylaxis in high 
risk patients. 

 Monitoring only by 
anti-Xa
5–10% cross reactivity 
with heparin

Hirudin (lepirudin) 0.4 mg/kg bolus
0.15 mg/kg/hr 
continuous infusion

1C Easily monitored 
by activated partial 
thromboplastin time 
(APTT)

Contraindicated in 
renal failure, allergic 
reactions

Fondaparinux 2.5–5 mg 2C Effect could be 
reversed by activated 
factor VII

Requires anti-Xa for 
monitoring, 



Clinically-Defined Maturity Onset Diabetes of the Young in Omanis 
 Absence of the common Caucasian gene mutations

394 | SQU Medical Journal, August 2011, Volume 11, Issue 3

both calves. The ventilation perfusion scan was 
indicative of pulmonary emboli. His blood count 
now showed Hb 11.2 g/dl, WBC 6.1 x 109, platelets 
49 x 109/l. The platelets decreased further to 25 x 
109/l during the next few hours. The coagulation 
screen was normal apart from elevated D-dimers. 
HIT testing using aggregation studies was positive. 
He was commenced on hirudin and his platelet 
count returned to normal on the sixth day when 
hirudin was stopped. He was anticoagulated with 
warfarin for a further 6 months. 

Case Five
A 74 year-old man was admitted for repair of an 
abdominal aortic aneurysm. His past medical 
history included hypertension, polycythaemia 
rubra vera and reflux oesophagitis. His counts 
prior to operation showed Hb 16.1 g/dl, WBC 7.8 
x 109/l, and platelets 139 x 109/l. He received UFH 
(minihep) prophylaxis pre- and postoperatively. 
One week postoperatively he became breathless 
and wheezy. A repeat blood count showed Hb 12.4 
g/dl, WBC 8.1 x 109/l, platelets 74 x 109/l, partial 
pressure of oxygen (pO2) 10.3, partial pressure of 
carbon dioxide (pCO2) 5.0, and phosphate buffered 
saline (pH) 7.43. Oxygen saturation was 92%. PT 
12.4 seconds, APTT 27.9 seconds, D-dimers >1.0 
<2.0. During the next 24 hours, his platelet count 
decreased further to 35 x 109/l and HIT testing 
was positive. A ventilation perfusion scan was 
indicative of multiple pulmonary emboli. He was 
anticoagulated with hirudin until his platelet count 

recovered to normal nine days later. He was then 
anticoagulated with warfarin.

Discussion
HIT is an antibody mediated reaction caused 
by exposure to heparin leading to devastating 
thrombotic complications.7,8 Following the 
administration of heparin, it binds to platelet 
factor 4 (PF4) triggering a humoral response and 
the formation of anti-platelet antibodies; these are 
generally IgG, although IgM and IgA antibodies have 
been reported.2,3,9 Evidence for the pathogenic role 
of platelet antibodies is strengthened by the typical 
onset of the syndrome after 5–15 days of heparin 
treatment. In vitro, the addition of serum from 
patients with HITS leads to platelet aggregation and 
platelet secretory response. This is the basis for the 
enzyme-linked immunosorbent assay (ELISA) test 
used in the diagnosis of HITS. PF4 released by the 
(α granules) of the platelets appears to be crucial in 
heparin induced platelet activation and binding to 
IgG.10,11 

t h r o m b o s i s & h e pa r i n
Heparin–PF4 complex binding to IgG leads to 
platelet aggregation and thrombocytopenia. 
The thrombosis, however, is thought to be due 
to platelet microparticles. Negatively charged 
heparin binds tightly to the positively charged 
protein tetramer PF4 leading to platelet activation 
and release of microparticles that are highly 
procoagulants, setting off the coagulation cascade 

Figure 1: Case Two (A) Multiple necrotic thigh lesions at site of heparin injection; (B - F) Bilateral gangreneous toes.



Salam Alkindi, Owen P Smith, Helen Enright

Case Report | 395

with further platelet activation/release.11,12 This 
leads to activation of thrombin and generation 
of  a hypercoagulable state. Acute inflammatory 
endothelial injury (seen in some surgical patients in 
particular), in connection with heparin associated 
IgG, may increase the generation of tissue factor 
leading to the activation of an intrinsic coagulation 
pathway. These two processes lead to thrombin 
activation/generation.12-16 Incidentally, our five 
patients had a recent surgical intervention prior to 
the development of this syndrome although medical 
patients can also develop this complication. This has 
led authorities in the field to suggest a double “HIT” 
is needed with simultaneous antigen exposure and 
proinflammatory signal in order to trigger a strong 
immune response.17

c l i n i c a l f e at u r e s
HITS should be suspected when the platelet count 
drops by 50% or more from the initial count prior to 
heparin therapy, although the absolute count may not 
drop below 150 x 109/l. However, the development 
of thrombosis, which can be either arterial or 
venous, cannot be predicted from the level of the 
platelet count.14,15 Thrombosis can occur at any 
site, but lower limbs, cardiac and central nervous 
systems are the most common sites resulting in limb 
gangrene, myocardial infarction or stroke. Other 
manifestations include skin necrosis in particular 
at the site of a subcutaneous heparin injection as 
seen in one of our patients. Haemorrhage and 
disseminated intravascular coagulations are rare, 
but recognised clinical features. Significantly all our 
patients showed evidence of thrombosis including 
DVT and pulmonary emboli; in one of them it 
was significant enough to cause a haemodynamic 
instability that could have resulted in death. Two 
of our patients showed evidence of bleeding and 
one of them developed skin necrosis [Figure 1]. 
It is interesting to note that one of our cases also 
had background of polycythaemia, a condition 
that is known to predispose to thrombosis. There 
have been similar previous reports of HITS with 
polycythaemia.18

d i a g n o s i s o f t h e c o n d i t i o n
When HITS is suspected, measures should be 
taken to confirm the diagnosis before major 
complications develop and to exclude other causes 
of thrombocytopenia. The most important aspect 

of the diagnosis is the clinical suspicion and 
demonstration of a drop of >50% in platelet level 
prior to the episode, even if the platelet level is still 
within the normal range. Warkentin has suggested 
the Warkentin’s “4Ts” pretest clinical scoring 
system which helps stratify patients into low, 
moderate and high pretest probability of HIT. It is 
based on the level of Thrombocytopenia, Timing of 
thrombocytopenia in relation to heparin exposure, 
Thrombosis and presence of another diagnosis to 
explain the Thrombocytopenia.19

There are two major diagnostic pathways: 
activation assays which measure platelet activation 
and include the platelets aggregation test (PAT), and 
serotonin release test (SRT). PAT is the most widely 
used laboratory screening test. It is based on the 
demonstration of platelet aggregation upon mixing 
patient serum with normal donor platelets in the 
presence of heparin. Although the test is specific, its 
sensitivity is only about 50%. The sensitivity could 
be improved by a) using the same sample of heparin 
which was used to treat the patient; b) using normal 
washed platelets, and c) screening the controls for 
arginine13,1 expressions as opposed to histidine 
which result in altered affinity in platelets Fc gamma 
RIIA.11,20 The SRT, on the other hand, is based on 
exposure of normal donor platelets to radioactive14 

C-serotonin and mixing it with recently heat 
inactivated patient serum and heparin. Platelet 
activation leads to increased release of serotonin 
and radioactivity. The limitation of this test is the 
need to use a radioactive substance, which a lot of 
laboratories try to avoid. Also, it requires time and 
the result may not be available quickly enough for a 
clinical decision; however, it has a sensitivity of 90% 
and a specificity approaching 100%. Flow cytometry 
is a promising alternative which avoids radioactivity, 
but it has not yet been widely adopted or evaluated 
for routine clinical testing.21-23 The antigen detection 
assay or ELISA based assay is used to assess 
the presence of antibodies against heparin/PF4 
complex. This test is gaining popularity, though it 
is associated with about 3–20% false positive results 
in the absence of thrombocytopenia or thrombosis. 
False negative results can occur particularly when 
antibodies against other than heparin/PF4 complex 
do exist;24 however, in general, it has an excellent 
negative predictive value.



Successful Use of Alternative Anticoagulants in the Management of Heparin-induced Thrombocytopenia with  
Thrombotic Complications 

Report of 5 cases and review of literature

396 | SQU Medical Journal, August 2011, Volume 11, Issue 3

m a n a g a m e n t

The mainstay of the management of HITS is that 
all forms of heparin, including LMWH should 
be stopped. Efforts should be made to establish 
the diagnosis and/or to exclude other causes of 
thrombocytopenia. Treatment is required for the 
original thrombotic process for which heparin was 
given, and for the treatment of the complications 
that follow the onset of HITS. There may be a case 
for prophylactic anticoagulation as over 50% of 
patients with isolated HITS subsequently develop 
thrombosis.

a lt e r n at i v e a n t i c o a g u l a n t s
There are two alternative anticoagulants 
danaparoid and hirudin. Danaparoid is composed 
of low molecular weight heparanoid comprising 
heparin sulphate (84%), dermatan sulphate (12%) 
and chondroitin sulphate (4%). It is different from 
heparin and LMWH in the degree of sulphation and 
molecular weight.4,20, 21,25 It is useful in thrombosis 
associated with heparin (both in arterial and 
venous types) and in coronary heart disease and 
haemodialysis. However, it is associated with 
a number of disadvantages particularly, 5–10% 
cross reactivity with heparin, bleeding with no 
available antidote, long half-life and it has no effect 
on thrombin. It also requires anti-Xa assay for 
its monitoring. The dose is not well established, 
however 2000 IU intravenous or SC as a bolus dose 
followed by 2000 IU twice daily is recommended for 
patients of average build. It is available in Europe, 
but not in the USA.

Hirudin is a leech-derived direct thrombin 
inhibitor peptide achieving an effective 
anticoagulation in HITS and without cross-
reactivity with heparin. Hirudin and other anti-
thrombins such as hiruko and argatroban have 
the advantage of easy monitoring of anticoagulant 
effects using APTT. It is given at a dose of 0.4 mg/
kg bolus followed by 0.15 mg/kg/hour continuous 
infusion and adjusted according to the desired 
APTT. It is metabolised by the kidneys thus it is not 
recommended in patients with renal failure, or in 
patients undergoing haemodialysis. 

Ancord is a potent defibrinogenating agent 
derived from the Malayan pit viper. It converts 
fibrinogen into abnormal non-crosslinked fibrin 
polymers that are cleaved rapidly and removed 
from the circulation. It is used in pulmonary 

thromboembolic disease, deep vein thrombosis and 
thrombosis complicating HITS. It is administered 
at a dose of 1 u/Kg by intravenous route and 
monitored using fibrinogen levels; however, 
it lacks any activity against thrombin which is 
increased in many patients with HITS. It also has 
an unpredictable effect on fibrinogen and does not 
achieve its anticoagulants effect rapidly.26

Fondaparinux (Arixtra) is composed of a 
modified pentasaccharide similar to heparin. 
Its selectively inhibits Xa and it was shown to be 
effective in HIT. Fondaparinux does not bind to 
PF4 and as such does not seem to cause HIT itself, 
although there have been some recent reports of 
HIT antibodies present without causing platelets 
depletion or thrombosis. Its effects could be 
theoretically reversed by recombinant activated 
factor VII.27

Warfarin is a useful oral agent, particularly 
when further anticoagulation is required; however, 
warfarin is not recommended until 5 days have 
elapsed from the onset of HITS, or the platelet 
counts have returned to normal. The use of warfarin 
early on in the acute phase can cause a precipitant 
drop in protein C levels causing further thrombosis; 
however, if the patient is already anticoagulated 
with warfarin, it may be continued.26

Other alternative treatments, including anti-
platelet agents such as aspirin, dipyridamole and 
dextran, have being used particularly to inhibit 
platelet aggregation and further platelet activation; 
however, they have no role in inhibiting thrombin 
activity and as such they are not routinely 
recommended. Plasmapheresis has also been 
suggested to remove the circulating abnormal IgG. 
Plateletpheresis has also been employed particularly 
to stop platelet destruction in a cardiopulmonary 
bypass situation. Intravenous immunoglobulin has 
also been used to treat HITS with some anecdotal 
success. Prophylactic platelet transfusions should be 
restricted to patients with active bleeding as giving 
platelets in this condition may worsen thrombosis. 

Conclusion
Heparin, although commonly used for management 
of thromboembolic disease, can be associated  
with very serious side effects including 
thrombocytopenia and thrombosis. HITS is 
frequently unrecognised until the development 



Salam Alkindi, Owen P Smith, Helen Enright

Case Report | 397

of a serious life or limb threatening thrombotic 
episode so platelets counts should be monitored 
regularly in patients receiving heparin. These cases 
demonstrate that HITS can occur with the use of all 
forms of heparin including prophylactic, low dose 
UFH and LMWH. Our data suggest that HITS is 
also seen with sodium heparin salts as opposed to 
calcium salts as reported previously. The use of an 
aggregation test is useful guide, but it is associated 
with a number of false negative results and the  
diagnosis has to remain a clinical one. Serological 
based testing is gaining momentum and its one of 
the most useful tests available. Prompt withdrawal 
of all forms of heparin including heparin flushes, 
or heparin impregnated intravascular catheters, 
is crucial to avoid further complications. Early 
introduction of alternative anticoagulation therapy 
is recommended when thrombosis is present, or 
the risk of developing thrombosis is high. Prompt 
recognition of this syndrome, discontinuation of 
all forms of heparin and institution of alternative 
anticoagulant therapy are the cornerstones of the 
successful management of this condition.

References
1. Cancio LC, Cohen DJ. Heparin-induced 

thrombocytopenia and thrombosis. J Am Coll Surg 
1998; 186:76–91.

2. Warkentin TE, Kelton JG. Temporal aspects of 
heparin induced thrombocytopenia. N Eng J Med 
2001; 344:1286–92.

3. DB Brieger, Mak KH, Marchant KK, Topol EJ. 
Heparin induced thrombocytopenia. J Am Coll 
Cardiol 1998; 31:1449–59.

4. Warkentin TE, Change BH, Greinacher A. Heparin-
induced thrombocytopenia: toward consensus. 
Thromb Haemost 1998; 79:1–7.

5. Gittoes NJL, Wilde JT, Sheppard MC, Ferner RE 
Heparin-induced thrombosis. Postgrad Med J 1997; 
73:684–5.

6. Prandoni P, Siragusa S, Girolami B, Fabris F. The 
incidence of heparin induced thrombocytopenia in 
medical patients treated with low molecular weight 
heparin. Blood 2005; 106:3049–54.

7. Szokol JW. Heparin-induced thrombocytopenia. 
Semin Cardiotho Vasc Anesth 2010; 14:73–4

8. Battistelli S, Genovese A, Gori T. Heparin-induced 
thrombocytopenia in surgical patients. Am J Surg 
2010; 199:43–51.

9. Wu KK, Phillip M, D’souza D, Hellums JD. Platelet 
activation and arterial thrombosis. Lancet 1994; 

344:991–5.

10. Pouplard C, May AM, Lochmann S, Amiral J, Vissac 
AM, Marchand M, et al. Antibodies to platelet factor 
4 heparin after cardiopulmonary bypass patients 
anticoagulated with unfractionated heparin or low 
molecular-weight heparin. Clinical implications for 
heparin induced thrombocytopenia. Circulation 
1999; 99:2530–6.

11. Arepally G, McKenzie SE, Jiang XM, Poncz M, 
Clines DB. FcγRIIA H/H131 polymorphism, a 
subclass-specific IgG anti-Heparin/platelet Factor 
4 antibodies and clinical course in patients with 
heparin induced thrombocytopenia and thrombosis. 
Blood 1997; 89:370–5.

12. Matsuo T, Tomaru T, Kario K, Hirokawa T. Incidence 
of heparin–PF4 complex antibody formation and 
heparin–induced thrombocytopenia in acute 
coronary syndrome. Thromb Res 2005; 115:475–81.

13. Visentin G, Ford SE, Scott JP, Aster RH. 
Antibodies from patients with heparin induced 
thrombocytopenia/thrombosis are specific for 
platelet factor 4 complexed with heparin or bound to 
endothelial cells. J Clin Invest 1994; 93:81–8.

14. Warkentin TE, Elavathil LJ, Hayward CP, Johnston 
MA, Russett JI, Kelton JG. The pathogenesis of 
venous limb gangrene associated with heparin 
induced thrombocytopenia. Ann Intern Med 1997; 
127:804–12.

15. Kelton JG, Warkentin TE. Heparin induced 
thrombocytopenia, Diagnosis, natural history and 
treatment options. Postgrad Med 1998; 103:169–79.

16. Lobenow N, Hinz P, Thomaschewski S, Lietz T, 
Volger M, Ladwig A, et al.  The severity of trauma 
determines the immune response to PF4/heparin and 
the frequency of heparin induced thrombocytopenia. 
Blood 2010; 115:1797–803.

17. Warkentin TE. HIT: More than just heparin. Blood 
2010; 115:1664–5. 

18. Hayashi T, Suyama Y, Kaneko M, Okamura J, 
Nakao Y, Nonakar Y, Nomura T. Heparin-induced 
thrombocytopenia and thrombosis in a patient with 
polycythaemia. Vera Inter Med 2004; 43:587–9.

19. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Greinacher 
A. Evaluation of pretest clinical score (4Ts) for the 
diagnosis of heparin-induced thrombocytopenia in 
two clinical setting. J Thromb Haemost 2006; 4:759–
65.

20. Buerger Th, Tautenhahn J, Meyer F, Lippert 
H. Heparin-induced vascular occlusion in 
vasculosurgical patients. J Cardiovasc Surg 1999; 
40:237–42.

21. Walenga JM, Bick RL. Heparin induced 
thrombocytopenia paradoxical thromboembolism 
and other side effects of heparin therapy. Med Clin 
N Am 1998; 82:635–58.

22. Gobbi G, Mirandola P, Tazzari PL, Talarico E, Caimi 
L, Martini G, et al. New laboratory test in flow 



Successful Use of Alternative Anticoagulants in the Management of Heparin-induced Thrombocytopenia with  
Thrombotic Complications 

Report of 5 cases and review of literature

398 | SQU Medical Journal, August 2011, Volume 11, Issue 3

cytometry for the combined analysis of serologic 
and cellular parameters in the diagnosis of heparin-
induced thrombocytopenia. Cytometry Part B 
(Clinical Cytometry) 2004; 588:32–8.

23. Tomer A, Masalunga C, Abshire TC. Determination 
of heparin-induced thrombocytopenia: a rapid 
flow cytometric assay for direct demonstration 
of antibody-mediated platelets activation. Am J 
Hematol 1999; 61:53–61.

24. Vitale M, Tazzari P, Ricci F, Mazza MA, Zauli G, 
Martini G, et al. Comparison between different 
laboratory tests for the detection and prevention 
of heparin-induced thrombocytopenia. Cytometry 
2001; 46:290–5.

25. Nicholson CD, Meuleman DG, Magnani HN, Egberts 
JFM, Leibowitz DA, Spinler SA, et al. Danaparoid 
is not a low molecular weight heparin. Am J Hosp 
Pharm 1994; 51:2049–50.

26. Lubenow N, Warkentin TE, Greinacher A, Wessel 
A, Sloane DA, Krahn EL, et al. Results of a systemic 
evaluation of treatment outcomes for heparin-
induced thrombocytopenia in patients receiving 
danaparoid, ancrod, and/or coumarin explain the 
rapid shift in clinical practice during the 1990s. 
Thromb Res 2006; 117:507–15.

27. Amiral J, Lormeau JC, Marfaing-Koka A, Vissac AM, 
Wolf M, Boyer-Neumann C, et al. Absence of cross 
reactivity of SR90107/A/ORG31540 pentasaccharide 
with antibodies to heparin-PF4 complexes developed 
in heparin-induced thrombocytopenia. Blood 
Coagul Fibrinolysis 1997; 8:114–7.

28. Savi P, Chong BH, Greinacher A, Gruel Y, Kelton 
JG, Warkentin TE, et al. Effects of fondaprinux on 
platelets activations in the presence of heparin 
dependent antibodies. A blinded comparative multi-
centre study with unfractionated heparin. Blood 
2005; 105:139–44.