Life-Threatening Intracranial Hemorrhage With Unexpectedly High Prothrombin Time Following Venous Thromboembolism Prophylaxis

Abstract

Effective thromboprophylaxis with low-dose subcutaneous heparin has been shown to reduce morbidity and mortality. Low-dose prophylactic heparin usually has very low bleeding risk and therefore, prothrombin time (PTT) monitoring or dose adjustment according to age, weight and renal function is not recommended. Life-threatening hemorrhage and markedly elevated PTT with prophylactic heparin is a very rare complication. An 86-year-old woman was admitted with urinary tract infection (UTI) and started on 5,000 U subcutaneous heparin three times a day. Patient condition improved but on day 3, she developed sudden onset of headache, confusion and drowsiness. CT of head showed massive intracranial bleed with midline shift. Craniotomy was done and hematoma was evacuated. PT/INR was normal but PTT was significantly prolonged. Rest of laboratory investigations were inconclusive which ruled out other important causes of elevated PTT and bleeding. Patient was given protamine sulphate and transfused fresh frozen plasma , packed red blood cells and platelets. Patient condition deteriorated and family decided to withdraw life support. Venous thromboembo-lism (VTE) prophylaxis may be complicated by hemorrhage especially in high risk patients. Heparin should be used cautiously and its effect should be monitored in such patients. Though low-dose unfractioned heparin thrice daily has been found to be superior to twice daily heparin in preventing thromboembolism, bleeding risk is higher.

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Case Report J Med Cases. 2015;6(7):313-317
ress
Elmer
Life-Threatening Intracranial Hemorrhage With Unexpectedly
High Prothrombin Time Following Venous Thromboembolism
Prophylaxis
Hassan Tahira, b, Adil Wania, Vistasp Daruwallaa
Abstract
Effective thromboprophylaxis with low-dose subcutaneous heparin has
been shown to reduce morbidity and mortality. Low-dose prophylactic
heparin usually has very low bleeding risk and therefore, prothrombin
time (PTT) monitoring or dose adjustment according to age, weight and
renal function is not recommended. Life-threatening hemorrhage and
markedly elevated PTT with prophylactic heparin is a very rare com-
plication. An 86-year-old woman was admitted with urinary tract infec-
tion (UTI) and started on 5,000 U subcutaneous heparin three times a
day. Patient condition improved but on day 3, she developed sudden
onset of headache, confusion and drowsiness. CT of head showed mas-
sive intracranial bleed with midline shift. Craniotomy was done and
hematoma was evacuated. PT/INR was normal but PTT was signi-
cantly prolonged. Rest of laboratory investigations were inconclusive
which ruled out other important causes of elevated PTT and bleeding.
Patient was given protamine sulphate and transfused fresh frozen plas-
ma, packed red blood cells and platelets. Patient condition deteriorated
and family decided to withdraw life support. Venous thromboembo-
lism (VTE) prophylaxis may be complicated by hemorrhage especially
in high risk patients. Heparin should be used cautiously and its effect
should be monitored in such patients. Though low-dose unfractioned
heparin thrice daily has been found to be superior to twice daily heparin
in preventing thromboembolism, bleeding risk is higher.
Keywords: Intracranial hemorrhage; Prolonged PTT; Venous throm-
boembolism; Low molecular weight heparin; Unfractionated heparin;
VTE prophylaxis
Introduction
Venous thromboembolism (VTE) is the collective term used
for deep vein thrombosis (DVT) and pulmonary embolism
(PE), which is the leading cause of signicant morbidity and
mortality in hospitalized patients with approximately 200,000
deaths each year from PE alone in US hospitals [1]. Low-dose
unfractionated heparin (LD-UFH) or low molecular weight
heparin (LMWH) is commonly used for VTE prophylaxis
and has been shown in various studies to reduce the risk of
thromboembolism. LD-UFH or LMWH does not cause signi-
cant prothrombin time (PTT) prolongation, hence regular PTT
monitoring is not recommended [2]. Life-threatening hemor-
rhage with low-dose subcutaneous heparin secondary to mark-
edly high PTT is a very rare complication. We report a case of
abnormally high PTT in an old lady who developed massive
intracranial hemorrhage after LD-UFH.
Case Report
An 86-year-old woman presented to emergency department
(ED) with generalized weakness. She was recently diagnosed
with urinary tract infection (UTI) which grew enterococcus
on culture, and she was started on nitrofurantoin. Patient was
unable to tolerate antibiotic and developed nausea, vomiting
and diarrhea. According to patient’s family, she had been hav-
ing off and on episodes of confusion and forgetfulness for last
few months for which outpatient CT of head was done recently
which did not show any acute changes (Fig. 1). It was thought
that her UTI might be contributing to her waxing and waning
altered mental state. Patient was unable to complete course of
nitrofurantoin and presented to ED with generalized weakness
and letharginess. Patient denied any fever, chills, cough, short-
ness of breath or chest pain.
She did not have any headache, neck pain or photophobia.
Patient also denied any frequency, urgency, dysuria or burning
micturation. She did have some light headedness which started
after multiple episodes of vomiting and diarrhea. Patient used
to live with her husband and was able to perform activities of
daily living. Past medical history was signicant for hyperten-
sion, cervical adenocarcinoma, hypothyroidism, osteoarthritis,
stress incontinence, aortic stenosis and venous insufciency.
Her home medications included baby aspirin, lisinopril, bu-
metanide, iron and multivitamins.
Patient was hypotensive with systolic blood pressure in
80s when she was brought to the emergency. Rest of the vitals
Manuscript accepted for publication May 20, 2015
aDepartment of Internal Medicine, Temple University/Conemaugh Memorial
Hospital, 1086 Franklin Street, Johnstown, PA 15905, USA
bCorresponding Author: Hassan Tahir, Department of Internal Medicine, Tem-
ple University/Conemaugh Memorial Hospital, 1086 Franklin Street, Johns-
town, PA 15905, USA. Email: htahir@conemaugh.org
doi: http://dx.doi.org/10.14740/jmc2193w

Articles © The authors | Journal compilation © J Med Cases and Elmer Press Inc™ | www.journalmc.org
314
Intracranial Hemorrhage J Med Cases. 2015;6(7):313-317
were stable. Urine analysis showed too numerous WBCs. Pa-
tient was given 2 L of normal saline bolus and 1 g of rocephin
intravenously. Patient’s blood pressure improved signicantly
after uid resuscitation. She was admitted in the hospital on
the suspicion of possible sepsis secondary to UTI. Urine cul-
ture was again positive for enterococcus which was sensitive
to penicillins. Blood and sputum cultures were negative for
any bacteria. All baseline tests including CBC, CXR, EKG,
serum electrolytes, renal and liver function were normal at the
time of admission other than albumin level which was low (2.1
g/dL). PT/INR and PTT were also within normal limits. Pa-
tient was continued on rocephin and most of her home medica-
tions including baby aspirin. Patient was started on subcutane-
ous 5,000 U unfractionated heparin three times a day for VTE
prophylaxis.
Patient condition improved during the hospital stay and
she was about to be discharged, when on day 3, she started
complaining of severe headache and subsequently became
acutely confused, lethargic and obtunded. Her blood pressure
was slightly high. A stat CT was obtained which showed bilat-
eral acute extra-axial hemorrhage, right signicantly greater
than left, with severe mass effect in the right cerebral hemi-
sphere and midline shift (Fig. 2). Patient was intubated and
immediately transferred to ICU. Patient was seen by neuro-
surgery that performed craniotomy and drainage of large right
acute subdural hematoma. A Jackson-Pratt drain (JP drain) was
placed to allow drainage of any accumulated blood. Repeat
laboratory investigations showed normal PT/INR but PTT was
elevated to > 100 (Table 1). Taking into account possible labo-
ratory error, PTT was repeated again which again came back
more than 100. Aspirin and subcutaneous heparin was immedi-
ately discontinued. D dimer, binogen and CBC were normal
and peripheral smear did not show any abnormal RBC mor-
phology. Similarly, liver functions and renal functions were
normal. Normal PTT at the time of admission with markedly
high PTT after starting subcutaneous heparin in the presence
of negative DIC panel led to the diagnosis of heparin-induced
intracranial hemorrhage. Patient was given protamine sulfate
and transfused 2 units of fresh frozen plasma (FFP). PPT was
repeated after 3 h which showed signicant fall in PTT (Table
1). In the mean time, patient’s hemoglobin also dropped to 8.6.
Two units of packed red blood cell (PRBC), one more unit of
FFP and one unit of platelets were transfused. Repeat CT scan
of head done next day showed persistent extra-axial hematoma
and severe parafalcine herniation much worse as compared
to previous scan (Fig. 3). Taking into account the deteriorat-
ing condition of patient and poor prognosis, family decided to
withdraw life support and continue only end of life care.
Discussion
DVT is dened by the formation of thrombus with in deep
Figure 2. Large right extra-axial hemorrhage with midline shift and small hemorrhage in left frontal region. There is also mild
bilateral subarachnoid hemorrhage.
Figure 1. CT of head done 1 week before admission showing no hem-
orrhage.

Articles © The authors | Journal compilation © J Med Cases and Elmer Press Inc™ | www.journalmc.org 315
Tahir et al J Med Cases. 2015;6(7):313-317
veins of legs that may extend higher into pelvic veins. Clot in
deep veins may dislodge and migrate to lungs where they can
impede blood ow in pulmonary artery or its branches leading
to a life-threatening condition called PE. The close association
between DVT and PE led to the use of term “VTE” that covers
both conditions. There are a number of risk factors for develop-
ing VTE, the most common being the old age, previous DVT,
immobility, cancer, acute infection, surgery and pregnancy [3].
Old age is an independent risk factor for VTE, which along
with immobilization and co-morbid medical conditions may
strikingly increase the risk of DVT, thus stressing the need of
adequate thromboprophylaxis in critically ill old patients [4].
Pharmacological VTE prophylaxis should be started in all
high risk patients after risk assessment. American College of
Chest Physicians (ACCP) recommends LD-UFH or LMWH
for patients with high risk of VTE [5]. Unfractionated heparin
is a complex mixture of glycosaminoglycans which binds to
antithrombin III to form a complex which in turn inactivates
factor IIa (thrombin) and factor Xa [2]. Inhibition of thrombin
causes elevation of PTT and that is the reason PTT levels are
used to monitor therapeutic unfractionated heparin therapy.
But in case of subcutaneous LD-UFH for VTE prophylaxis,
PTT elevation is very mild and risk of bleeding is low, thus
regular PTT monitoring is not recommended. PTT is a per-
formance indicator of the efcacy of both the intrinsic and
the common coagulation pathways. The most common causes
of prolonged PTT are therapeutic heparin therapy, liver dis-
ease, DIC, factor inhibitors and inherited or acquired factor
deciencies. The PTT may not be prolonged until the factor
levels have decreased to 30-40% of normal and that is why
low-dose subcutaneous heparin does not lead to signicant
prolongation of PTT as it does not produce sufcient blood
levels to signicantly decrease coagulation factors. Heparin
has a shorter half life and has variable and extensive binding
to plasma proteins and reticuloendothelial system (RES), thus
producing a variable response. RES plays an important role
in the clearance of unfractionated heparin. On the other hand,
LMWH is formed by the fractionation of heparin molecules
with less protein binding, dose-independent clearance and bet-
ter bioavailability. These features produce a longer half life
and make anticoagulant response of LMWH more predictable.
LMWH interacts less readily with platelet factor 4, decreasing
the risk of heparin-induced thrombocytopenia, a complication
of some patients receiving heparin therapy [6]. LMWH has
more effect on inhibiting factor Xa and hence does not increase
PTT at therapeutic doses. Once daily dosing and more predict-
able anticoagulation affect makes it the pharmacological VTE
prophylaxis of choice for many physicians. LMWH is cleared
by kidneys and therefore it is not recommended in patients
with kidney disease, thus making LD-UFH as the only choice
in such cases.
Both unfractionated heparin and LMWH have been shown
to reduce the risk of VTE but recent data suggest that LMWH
might be slightly more effective in reducing thrombosis as
compared to unfractionated heparin with same risk of bleeding
[7]. In addition, a meta-analysis of randomized controlled tri-
als suggested that LMWH might have better safety prole with
less risk of bleeding [8]. Unfractionated heparin, on the other
hand, can produce variable and unpredictable effects depend-
ing on its bioavailability and clearance. Thrice daily dosing vs.
Figure 3. Post-surgical CT of head showing persistent acute on chronic extra-axial hematoma. There is increase in the size of
left frontal lobe hematoma. Note severe parafalcine herniation much worse than the previous CT scan.
Table 1. Laboratory Investigations From Day of Admission
Labs On admission 3 days later 4 days later
Hemoglobin 12 10 8.9
WBC 3.5 3.6 7.0
Platelets 172 168 196
PT/INR 10.6/1.0 10.4/1.0 10.4/1.0
PTT 29 > 100. Repeat PTT was again > 100. PTT was 83 after 1 unit of FFP. 53

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316
Intracranial Hemorrhage J Med Cases. 2015;6(7):313-317
twice daily dosing of unfractionated heparin has always been
a topic of hot debate. Most recent ACCP guidelines recom-
mend using LD-UFH without specifying frequency or dose.
Various studies and meta-analysis have been done to compare
efcacy and bleeding risk between twice and thrice daily hepa-
rin dose. A meta-analysis of 12 randomized controlled studies
concluded that thrice daily LD-UFH appeared to be superior to
twice daily heparin in preventing thromboembolism; however,
bleeding risk was higher [9]. Therefore, risk vs. benet should
always be taken into account and heparin frequency decided
accordingly. Heparin 5,000 U twice a day may be a better op-
tion for those who are at increased risk of bleeding.
Signicant bleeding with very high PTT following VTE
prophylaxis is a very rare complication. Elevated PTTs dur-
ing LD-UFH have been reported previously [10, 11]. But life-
threatening intracranial hemorrhage with markedly high PTT
after low-dose heparin prophylaxis has not been recognized
before. A number of factors can increase and prolong hepa-
rin action resulting in signicant elevation of PTT following
low-dose heparin VTE prophylaxis, thus increasing the risk
of bleeding. These factors include old age, low weight, low
plasma proteins and abnormal liver and renal functions [2]. In
one study, longer PTTs were associated with < 70 kg weight,
age > 65 years, female sex, and black race; shorter PTTs were
associated with diabetes and smoking [12]. Risk of bleeding
is more with unfractionated heparin due to its unpredictable
and variable anticoagulation response. In patients with above
risk factors, heparin 5,000 U twice a day or LMWH might be
a better option.
Our patient presented with UTI and was considered at very
high risk for VTE due to old age, infection, immobility and
malignancy. She was started on 5,000 U subcutaneous unfrac-
tionated heparin three times a day. On day 3, patient developed
massive intracranial hemorrhage with midline shift. The most
noticeable laboratory nding was signicantly prolonged PTT.
Our differential diagnosis included heparin overdose, DIC, liv-
er disease, lupus anticoagulant and coagulation factor decien-
cies. Extensive workup was done to rule out each differential
diagnosis. Patient’s PTT was normal on admission and she did
not have any bleeding tendency in past, so inherited disorders
were ruled out. Thrombin time (TT) was prolonged and repti-
lase time (RT) was normal. Mixing studies did not show any
factor inhibitors. DIC was a likely possibility because patient
had UTI. Blood cultures were negative and laboratory tests
were inconclusive with normal platelets, brinogen, D dim-
mers and peripheral blood smear. Rest of lab tests including
liver, renal function tests and lupus anticoagulant were normal.
Results of above tests and elevated PTT after starting subcu-
taneous heparin further reinforced our suspicion of heparin
overdose as the cause of bleeding. The patient was not on any
NSAIDs or blood thinners before admission to hospital. All
nursing notes and doctor’s orders were reviewed to nd out the
triggering factor for heparin overdose. Saline not the heparin
ushes were used to clear intravenous and central lines. No
mistake was found on the part of nurses regarding dose miscal-
culation or accidently administering heparin intravenously in-
stead of subcutaneously. Laboratory error was a possibility and
every effort was made to nd out any possible error. Accurate
sample collection, handling, transportation, processing and
storage were done, thus minimizing pre-analytical laboratory
error. Similarly, analytical errors were avoided by using appro-
priate test methodologies and by incorporation of appropriate
control measures. Still PTT was repeated to rule out any labo-
ratory error which came back again very high. Patient history
was carefully reviewed to nd out anything unusual that might
be contributing to heparin overdose. As unfractionated heparin
was used, it is already known to have variable and unpredict-
able effects as compared to LMWH. Old age, low albumin, ag-
ing reticuloendothelial system and low weight were the factors
in our patient which might have contributed to decreased clear-
ance of LD-UFH. In addition, thrice daily dosing was used as
VTE prophylaxis which in recent studies has been shown to
increase bleeding risk especially in old patients. Patient was
also on baby aspirin which also increased the bleeding risk. We
believe that delayed clearance of LD-UFH was the main factor
responsible for life-threatening bleeding in our patient.
Conclusion
The purpose of this case report is not to discourage medical
practitioners from VTE prophylaxis as effective thrombo-
prophylaxis can safely reduce the incidence of VTE decreasing
the morbidity and mortality. In fact, our sole purpose is to warn
doctors about the possibility of life-threatening hemorrhage
with low-dose subcutaneous heparin. Very old people, on one
hand, are at increased risk of DVT, but, on the other hand,
they are also at increased risk of bleeding especially those hav-
ing comorbid conditions. PTT monitoring is not recommended
with VTE prophylaxis, but it should be considered in selected
high risk patients especially very old (> 80 years). If kidney
functions are normal, LMWH could be a better choice due to
its more predictable effect and low risk of bleeding. But if LD-
UFH is started, heparin twice daily instead of thrice daily might
be a safe option in such high risk patients. Further studies are
needed to evaluate the dose and type of pharmacologic throm-
boprophylaxis in special patient populations. The prophylactic
use of heparin can become safer if appropriately used, effect is
monitored and its pharmacokinetics is considered.
Competing Interests
Authors conrm that they have no competing interests.
Abbreviations
VTE: venous thromboembolism; DVT: deep vein thrombosis;
PE: pulmonary embolism; LD-UFH: low-dose unfractionated
heparin; LMWH: low molecular weight heparin; PTT: pro-
thrombin time
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