Key Clinical message
- Glanzmann Thrombasthenia does not protect from venous thrombosis in
MPN
- we hypothesize on other mechanisms of thrombosis in MPN
- dabigatran can be given in a patient with Glanzmann Thrombasthenia
To the editor,
Glanzmann thrombasthenia (GT) is a rare autosomal recessive platelet
disorder characterized by a lack of functional integrins αIIb or β3. The
clinical phenotype is dominated by an increased mucocutaneous bleeding
tendency.1 The occurrence of venous thrombosis in
these patients is very rare, but a total of 12 case reports have been
published.2,3
We describe a 74-year old woman with GT caused by compound
heterozygosity for a pathogenic missense mutation
(c.1787T>C p.(Ile596Thr)) and a donor splice site mutation
(c.2841+1G>T p.(?)) in the ITGA2B gene. Her medical history
is extensive, and her bleeding score (ISTH-BAT) was 22 in 2016. She
suffered from hypertension for several years and smoked 5 cigarettes a
day for over 20 years, but stopped smoking in 2011. She has had multiple
episodes of mild microcytic anemia since 2014, for which she undergoes
regular colonoscopies for surveillance of adenomas. In March 2016, she
developed a superficial thrombophlebitis of her right calve after a long
car drive, which was treated with 200mg celecoxib once daily for 4
weeks. In April 2016 she had angina pectoris with ischemic abnormalities
on the electrocardiogram. An MRI-heart with adenosine showed
baso-inferoseptal and baso-anteroseptal perfusion defects. She was
treated with statins, metoprolol and amlodipine, but platelet inhibitors
were contraindicated due to her GT. Treatment was successful, and she
remains free of cardiac complaints until today. In October 2017, she
developed another thrombophlebitis in her left calve, for which
treatment with celecoxib for 4 weeks was started again. In February
2018, after a mild pneumonia, a deep vein thrombosis (DVT) was diagnosed
in the right leg, extending from the popliteal vein to the distal
external iliac vein. Her blood count at that time showed a mild
microcytic anemia (hemoglobin 9.0 g/dL) with normal leucocyte and
platelet counts. CT-thorax/abdomen showed no malignancies;
antiphospholipid antibodies were negative. Treatment with 110mg
dabigatran twice daily was started for 3 months. Two weeks after
stopping dabigatran, an exacerbation of her microcytic anemia was
detected that resolved after iron suppletion. In September 2018, a new
DVT occurred in the left leg, for which dabigatran was restarted. After
3 months, dabigatran was reduced to once daily 110mg for long term use.
She experienced no increase in bleeding tendency and is on dabigatran
since. A year later, in October 2019, she had higher hemoglobin values
than she was used to (hemoglobin 14.7 g/dL), her platelet count, which
was always in the normal range, increased to 599x109/L
and a mild leucocytosis developed (11.9x109/L). A JAK2
mutation was found (c.1849 G>T; p.Val617Phe) and the
diagnosis polycythemia vera was made. To prevent further thromboembolic
disease, low dose hydroxyurea treatment (500mg daily) was started, and
her blood count normalized within two weeks. Meanwhile, she showed
slight progression of DVT in her legs, after which dabigatran was
increased to twice daily 110mg. A year later, in Dec 2020, she had
progression of DVT, after which dabigatran was increased from twice
daily 110mg to twice daily 150mg. To date, she is without complaints and
tolerates both dabigatran and hydroxyurea very well.
Philadelphia chromosome negative myeloproliferative neoplasms (MPNs)
include polycythemia vera, essential thrombocytosis (ET) and
myelofibrosis. The hallmark of MPN is a dysregulation of cellular
processes in bone marrow precursors. Thrombosis frequently occurs in
MPNs. Well known risk factors are age and prior thrombosis. In addition,
hematocrit, leucocytosis, smoking and hypertension all independently
contribute to thrombotic risk in MPNs,4, 5 although
they are not incorporated in the current thrombotic risk stratification
model. There is a clear link between both leucocytes and red blood cells
and activation of the coagulation system in MPNs. Activated monocytes in
MPN show increased surface tissue factor expression, which is the
principal component in the extrinsic pathway of coagulation and
erythrocytosis causes blood flow stasis, leading to endothelial injury
and hypercoagulability. Erythrocytosis also leads to high shear stress
condition within the vessel, leading to platelet activation and
microparticle release.
As the key finding in ET is thrombocytosis, it is plausible that
platelets contribute to thrombotic risk in MPNs. The efficacy of
platelet inhibitors for primary prevention of thrombosis in MPNs further
supports an important role for platelets in MPN-associated venous
thrombosis.
Nevertheless, there is no clear correlation between platelet count and
thrombotic risk in ET,5 although there are reports of
altered platelet reactivity.6-10 This case report
clearly demonstrates that platelet aggregation through integrin αIIbβ3
does not contribute to venous thrombosis in MPNs. This is supported by
the observation that platelet aggregates are not dominantly present in
venous thrombi. Instead, platelets adhere either directly to the
activated endothelium or to adherent leukocytes, forming small
heterotypic aggregates. Platelet recruitment to the venous thrombus
depends on the interaction between GPIbα and exposed
VWF.11
How then, would platelets contribute to thrombosis in MPNs?
The interplay between platelets and the coagulation system in thrombus
formation appears to be pivotal. It has been demonstrated that αIIbβ3
deficient platelets aggregate if fibrin formation is
allowed.12 This fibrin-dependent platelet aggregation
is thought to be mediated by glycoprotein VI (GPVI).13Indeed, GPVI has been identified as a promising antithrombotic target as
GPVI deficiency protects against thrombosis while not interfering with
normal hemostasis.14 Activated platelets subsequently
provide a surface on which the coagulation reaction can propagate.
Moreover, they secrete both activated factor V and polyphosphates,
greatly enhancing the coagulation reaction.
Platelet-leucocytes complexes also play a significant role in venous
thrombosis. New evidence shows that CTL2 (choline transporter-like
protein 2, also known as SLC44A2) on the surface of neutrophils drives
neutrophil recruitment, activation and NETosis in vivo , and that
CTL2 is directly bound by activated
αIIbβ3 integrins on platelets in a
flow-dependent manner in vitro. 15 Especially in
MPN, exacerbated response to Toll Like Receptor stimulation is suggested
to promote platelet/leukocyte/endothelial interactions and secretion of
inflammatory mediators, reinforcing the thromboinflammatory
state.16 However, the lack of
αIIbβ3 integrins in GT suggests that
platelet-leucocyte complexes do not play an important role in MPN
related VTE.
In this case, MPN was diagnosed after the occurrence of VTE. Hence,
primary prevention was not an issue. However, if we would have found MPN
before she developed VTE, we still would not have started antiplatelet
therapy, in the assumption that her M. Glanzmann would provide a natural
protection against VTE. We decided to treat the VTE with a DOAC, as the
superiority of DOACs over vitamin K antagonists in terms of safety is
demonstrated.17 We used a dose of 110mg twice daily,
as also recommended by the manufacturer in patients with an increased
bleeding risk. Unfortunately, our patient had progression of VTE for
which the dose of dabigatran was increased twice. She did not experience
any bleeding episodes in 2 years of follow up. We are not aware of other
patients with GT currently treated with a DOAC. We do like to point out
that this is a unique case, where the procoagulant activity is
pronounced, perhaps counterbalancing the bleeding risks with a DOAC
here.
In summary, this case shows that the platelet
αIIbβ3 integrin is not involved in the
pathogenetic mechanism of relapsing venous thrombosis in MPN. This might
argue for further interest in the therapeutic role of GPVI inhibition.