Introduction
Platelets are critical cellular components in hemostasis and thrombosis with additional
roles in immunity and inflammation.[1 ] During primary hemostasis, platelets adhere to the damaged vessel wall and form
an initial wound-sealing plug upon activation and aggregation. During secondary hemostasis,
activated platelets provide a catalytic surface for coagulation reactions to support
thrombin generation and fibrin deposition. Thus, hemostasis is substantially impaired
in patients with significant thrombocytopenia, resulting in an increased risk of spontaneous
or trauma-/surgery-induced bleeding.
Platelet adhesion and aggregation are also critical events in arterial thrombus formation
when rupture of an atherosclerotic plaque leads to the exposure of collagen and other
thrombogenic material to the flowing blood. For this reason, pharmacological inhibition
of platelet function is standard of care in patients with cardio- or cerebrovascular
disease. In addition, platelets are involved in the pathophysiology of venous thromboembolism
(VTE), a composite of deep vein thrombosis (DVT) and pulmonary embolism (PE), although
anticoagulants, and not antiplatelet agents, are generally used to prevent or treat
VTE. Since both thrombocytopenia and antithrombotic drugs increase the risk of bleeding,
the management of vascular thrombosis in patients with low platelet counts is particularly
challenging in daily practice.[2 ]
Thrombocytopenia is defined as a platelet count below the lower limit of the normal
reference range, that is, a platelet count of less than 150 × 109 /L. Since platelet counts of 100–150 × 109 /L are not clinically relevant, thrombocytopenia is sometimes also considered as a
platelet count of less than 100 × 109 /L. For this article, the following severities of thrombocytopenia are defined, with
categorization according to the Common Terminology Criteria for Adverse Events (CTCAE)
of the National Cancer Institute (NCI), version 5.0, provided in brackets:
Mild thrombocytopenia—platelet count 75–150 × 109 /L (grade 1).
Moderate thrombocytopenia—platelet count 50–75 × 109 /L (grade 2).
Moderate-to-severe thrombocytopenia—platelet count 25–50 × 109 /L (grade 3).
Severe thrombocytopenia—platelet count < 25 × 109 /L (grade 4).
Regarding the underlying pathophysiology, three different mechanisms may lead to thrombocytopenia:
Decreased platelet production (e.g., aplastic anemia, vitamin B12 /folic acid deficiency, chemotherapy).
Increased platelet consumption (e.g., disseminated intravascular coagulation [DIC],
thrombotic microangiopathy [TMA], antibody-mediated platelet destruction/clearance).
Altered platelet distribution (e.g., hemodilution during pregnancy, splenomegaly).
Recognizing the dominant mechanism of thrombocytopenia has significant implications
for the management of patients with vascular thrombosis and low platelet counts. First,
in patients with thrombocytopenia due to decreased platelet production, low platelet
counts are also likely associated with impaired platelet function, because maturation
and proliferation of bone marrow megakaryocytes are significantly altered. In contrast,
thrombocytopenia due to accelerated platelet clearance may be associated with increased
proportions of hyperreactive immature platelets resulting from compensatory stimulation
of healthy megakaryocytes. Thus, depending on the predominant pathomechanism, the
overall bleeding risk may vary between patients with similarly low platelet counts.
Determination of the immature platelet fraction (IPF), which represents the release
of reticulated platelets from stimulated megakaryocytes, may help differentiate between
impaired production and increased destruction/clearance of circulating platelets as
the underlying cause of thrombocytopenia ([Fig. 1 ]).[3 ] Second, knowledge of the expected duration of thrombocytopenia and the availability
of symptomatic or causative treatment options to increase or correct platelet counts
is of utmost importance for assessing the bleeding risk and for tailored prescription
of antithrombotic agents.
Fig. 1 Assessing the immature platelet fraction (IPF), e.g., by flow cytometry, may help
distinguish between different causes of thrombocytopenia. In healthy controls, IPF
ranges of 1–18% (mean values, 7–8%) have been reported.[17 ]
In the absence of robust clinical trial data, this article aims at summarizing the
available empirical evidence on how to approach a patient with thrombocytopenia and
vascular thrombosis, acknowledging that tools on how to assess the competing risks
of bleeding and thrombosis in such a scenario have recently been reviewed.[2 ] In addition, specific hematological disorders characterized by both low platelet
counts and a thrombogenic state are highlighted, because their knowledge and recognition
have significant implications for diagnosis and treatment.
Patients with Cancer and Thrombocytopenia
Patients with solid cancers or hematological malignancies have a significantly increased
risk for both thromboembolic events and bleeding complications. Thrombocytopenia is
a frequent finding in oncological patients and may be caused by the malignancy itself
or its treatment with cytotoxic agents. Considering that the normal average lifespan
of circulating platelets is 8–10 days, platelet counts typically start to decline
on day 7 following initiation of myelosuppressive therapy, with a nadir reached at
day 14 and a gradual return to baseline levels by days 28–35.[4 ] The frequency of thrombocytopenia associated with select cancer types and cytotoxic
agents has recently been reviewed,[5 ] with grade 3/4 thrombocytopenia occurring, for example, in 8.6% of patients with
biliary tract cancer treated with gemcitabine/cisplatin combination chemotherapy and
57% of patients with bladder cancer treated with the same regimen.
Management of Venous Thromboembolism
When approaching a thrombocytopenic patient with cancer-associated VTE, thrombus burden,
clinical symptoms, and the timing of thrombocytopenia relative to the occurrence of
VTE should be considered in addition to absolute platelet counts ([Table 1 ]).[5 ]
[6 ]
[7 ]
[8 ] In patients with a platelet count of ≥50 × 109 /L, therapeutic-dose anticoagulation with low-molecular-weight heparin (LMWH) or a
direct oral anticoagulant (DOAC) is generally considered acceptable. In patients with
a platelet count of less than 50 × 109 /L and acute VTE, that is VTE occurring within the previous 4 weeks, a transfusion
strategy may be considered to allow for therapeutic-dose anticoagulation as long as
platelet counts are increased to more than 40–50 × 109 /L. This strategy appears particularly justified in patients with a large thrombus
burden (e.g., extensive proximal DVT or massive PE) and/or significant clinical symptoms
(e.g., dyspnea without exertion, tachycardia, hypotension, massive leg edema). In
case a transfusion strategy is not available or inefficacious, parenteral anticoagulation
with LMWH at intermediate, half-therapeutic dosages may be an option in patients with
acute VTE and a platelet count of 25–50 × 109 /L. This also applies to patients with chronic VTE, that is, VTE occurring more than
4 weeks ago, who have already received adequate anticoagulation prior to thrombocytopenia
to sufficiently resorb or consolidate intravascular thrombus manifestations, and in
whom prophylactic anticoagulation with LMWH at dosages approved for situations with
a high risk of VTE may also be acceptable. In patients with acute or chronic VTE and
a platelet count of less than 25 × 109 /L (grade 4), withholding anticoagulation or prophylactic dosages of LMWH are generally
recommended. Insertion of a retrievable inferior vena cava (IVC) filter, accompanied
by LMWH thromboprophylaxis when acceptable, may be an option only in highly symptomatic
patients with a large thrombus burden. Due to significant risks associated with the
procedure, the decision to place IVC filters should be based on careful discussion
by a multidisciplinary team considering patient values and preferences.
Table 1
Recommendations for the management of VTE in cancer patients with thrombocytopenia
Risk of VTE progression/recurrence
Platelet count
High[a ]
Low
≥50 × 109 /L
Full-dose, therapeutic anticoagulation (LMWH or DOAC)
25–50 × 109 /L
Full-dose, therapeutic anticoagulation (LMWH or DOAC) with platelet transfusion support
(target platelet count, > 40–50 × 109 /L)[b ]
Reduced-dose, e.g., half-therapeutic or prophylactic anticoagulation (LMWH)
< 25 × 109 /L
No anticoagulation or prophylactic LMWH[c ]
Abbreviations: DOAC, direct oral anticoagulant; LMWH, low-molecular-weight heparin;
VTE, venous thromboembolism.
Source: Adapted from various studies.[5 ]
[6 ]
[7 ]
[8 ]
a Risk of VTE progression/recurrence is considered high in patients with acute VTE
(< 4 weeks), particularly in those with large thrombus burden and/or significant clinical
symptoms.
b If a transfusion strategy is not feasible, anticoagulation with LMWH at reduced (e.g.,
half-therapeutic) dosages should be used.
c On rare occasions (e.g., in highly symptomatic patients with large thrombus burden),
insertion of a retrievable inferior vena cava filter may be considered.
Treatment of hematological malignancies is associated with extensive periods of thrombocytopenia
due to aggressive cytotoxic regimens and/or bone marrow failure inherent to the blood
cancer. In a retrospective analysis of 82 patients with hematological disorders experiencing
VTE during grade 3/4 thrombocytopenia, mostly patients with acute myeloid leukemia
and central venous catheter (CVC)-related thrombosis, 82% (n = 67) had been treated with anticoagulants and 88% (n = 59) had been managed with transfusion support to achieve a platelet count of ≥50 × 109 /L.[9 ] VTE progression/recurrence was documented in seven patients (8.5%) and any bleeding
event, predominantly grade 2 according to the World Health Organization (WHO) criteria,
in 31 patients (37.8%). Eleven patients (13.4%) suffered from transfusion reactions,
and 30 patients (36.6%) had to be treated with diuretics or dialysis for volume overload.
Of note, most bleeding events occurred when the platelet count was ≥50 × 109 /L. Taken together, these findings show that patients with blood cancer-associated
VTE and thrombocytopenia represent a particularly vulnerable population with significant
risks for recurrent thrombosis and transfusion-related adverse outcomes. In such patients,
platelet count–adjusted LMWH dosing (in acute VTE) or temporarily withholding anticoagulation
(in chronic VTE) are reasonable options.[10 ]
[11 ]
A retrospective management study supports an individualized, risk-adapted approach
to cancer patients with acute VTE and thrombocytopenia. While subtherapeutic LMWH
dosages were generally preferred in patients with platelet counts of less than 100 × 109 /L or the presence of cerebral metastasis, patients with PE or symptomatic VTE were
more likely to receive therapeutic-dose anticoagulation.[12 ]
Management of Arterial Thrombosis
Expert guidance is available for the management of antiplatelet therapy in acute coronary
syndrome (ACS) patients with thrombocytopenia.[13 ] General measures to reduce the bleeding risk include avoidance of nonsteroidal anti-inflammatory
drugs, utilization of proton pump inhibitors (PPIs) unless contraindicated, preference
of a radial approach for percutaneous coronary intervention (PCI), preference of second-generation
drug-eluting over bare-metal stents, restriction of dual-antiplatelet therapy (DAPT)
to 1 month after PCI, avoidance of glycoprotein (GP) IIb/IIIa inhibitors and of triple
therapy in patients with an indication for oral anticoagulation (OAC), and use of
lower doses (i.e., 75–100 mg per day) instead of higher doses of acetylsalicylic acid
(ASA). In patients with a platelet count of less than 50 × 109 /L or active bleeding, stopping all antiplatelet agents and avoidance of PCI are suggested.
In patients with a platelet count of ≥50 × 109 /L and no active bleeding who undergo PCI, DAPT for 1 month followed by clopidogrel
monotherapy together with PPI appears reasonable. In case PCI is not an option, clopidogrel
monotherapy and PPI are suggested.
More aggressive antiplatelet therapy may be warranted in ACS patients with cancer-associated
thrombocytopenia due to the inherent hypercoagulable state of malignancy.[14 ]
[15 ] In such patients, ASA monotherapy is an option when the platelet count is more than
10 × 109 /L, and DAPT with ASA and clopidogrel may be considered when the platelet count is
30–50 × 109 /L. Ticagrelor, prasugrel, and GPII/IIIa inhibitors are suggested only when the platelet
count is more than 50 × 109 /L. Duration of DAPT should be decided on after careful risk–benefit analysis and
multidisciplinary discussion. A similar approach appears reasonable in thrombocytopenic
cancer patients with atherothrombotic stroke who have an indication for DAPT.
Specific Hematological Disorders
Immune Thrombocytopenia
Immune thrombocytopenia, or idiopathic thrombocytopenic purpura (ITP), is caused by
autoantibody formation against platelet GPs with increased platelet destruction and
phagocytic clearance by reticuloendothelial cells, mainly located in the spleen.[16 ] Although acute pediatric ITP is typically self-limiting and preceded by viral infections
or vaccinations, adult ITP may evolve into a chronic disorder requiring treatment
in case of significant thrombocytopenia and/or bleeding symptoms. Diagnosis of ITP
is primarily based on the exclusion of other causes of thrombocytopenia and may involve
bone marrow biopsy or aspiration cytology. The role of detecting platelet GP-specific
antibodies is unclear.[17 ] Although relative thrombopoietin deficiency contributes to impaired megakaryocytopoiesis,
patients with ITP have increased IPFs and may thus present with a comparably mild
bleeding phenotype despite profound thrombocytopenia. Although platelet activation
is not a characteristic feature of ITP, the disorder is associated with an increased
incidence of venous and arterial thrombosis.[18 ] While classical (e.g., advanced age, obesity, hormonal contraceptives, pregnancy/puerperium,
cancer, recent surgery, history of VTE) and treatment-related risk factors (e.g.,
corticosteroids, high-dose intravenous immunoglobulins [IVIGs], splenectomy) contribute
to the etiopathogenesis of VTE in ITP, thrombocytopenia does not protect against thrombosis.[19 ] Likewise, anticoagulation seems to be feasible in most patients with ITP and VTE
despite persistently low platelet counts, which is consistent with a bleeding protective
effect of increased IPFs.[19 ]
Expert guidance on how to approach ITP patients with VTE or arterial thrombosis has
recently been published.[20 ] Similar to patients with cancer-associated VTE, full-dose anticoagulation with LMWH
or DOACs is considered acceptable in patients with a platelet count of greater than
50 × 109 /L. In patients with a platelet count of 25–50 × 109 /L, reduced-dose anticoagulation with LMWH is the preferred strategy, with unfractionated
heparin (UFH) being an option in patients with unstable thrombocytopenia and/or a
perceived high risk of bleeding due to its shorter half-life and the more predictable
reversibility of its anticoagulant effect by protamine administration. DOACs may be
an option on a case-by-case basis. In patients with a platelet count of less than
25 × 109 /L, specific ITP treatment should be considered to elevate the platelet count to more
than 50 × 109 /L. In refractory cases, the management of VTE must be highly individualized and based
on a particularly thorough risk assessment. In patients with ITP and arterial thrombosis
such as ACS, DAPT, preferably with ASA and clopidogrel, may be used when the platelet
count is greater than 50 × 109 /L, while single-antiplatelet therapy is recommended when the platelet count is 25–50 × 109 /L. Similar to patients with VTE, specific ITP treatment should be considered when
the platelet count is less than 25 × 109 /L. In patients with refractory ITP and a platelet count of greater than 10 × 109 /L, the authors of this article consider monotherapy with ASA an option, when the
risk of bleeding is considered to be low. Individual patients with platelet counts
of 25–50 × 109 /L may also be candidates for DAPT (e.g., patients < 60 years of age without relevant
comorbidities such as renal impairment, uncontrolled hypertension, or gastrointestinal
ulcerations).
Antiphospholipid Syndrome
The antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by
arterial, venous, and/or microvascular thrombosis in the presence of persistently
elevated antiphospholipid antibodies (aPLs).[21 ] In routine diagnostics, aPLs include IgG/IgM antibodies to cardiolipin or β2 -glycoprotein-I (β2 -GPI) and the lupus anticoagulant (LA). Additionally or alternatively to vascular
thrombosis, APS may be associated with obstetrical complications such as recurrent
early miscarriages, late fetal loss, or preterm delivery due to preeclampsia or intrauterine
growth restriction. Although not part of the main diagnostic criteria for definite
APS,[22 ] thrombocytopenia is a frequent finding in APS patients with a prevalence of 20–40%.[23 ] Low platelet counts may be caused by accelerated autoantibody-mediated platelet
destruction/clearance as observed in ITP or, possibly, by increased consumption due
to the hypercoagulable state. Consistent with the latter pathomechanism, APS-associated
thrombocytopenia may improve or completely resolve following initiation of efficacious
antithrombotic therapy.[24 ]
[25 ]
Anticoagulation with a vitamin K antagonist (VKA) is the treatment of choice in APS
patients with arterial thrombosis and patients with VTE who have a high-risk (i.e.,
triple- or LA-positive) aPL profile. Low-dose ASA may be considered in APS patients
with arterial thrombosis and a low-risk aPL profile or a high risk of bleeding, such
as in those with significant thrombocytopenia.[26 ] According to a consensus statement of different German medical societies, standard-dosed
DOACs are an option in patients with VTE and isolated cardiolipin and/or β2 -GPI antibodies.[27 ] Addition of low-dose ASA to VKA therapy may be considered upfront in high-risk APS
patients with arterial thrombosis or as an adjunct to OAC in patients with recurrent
arterial events.[26 ]
Catastrophic APS (CAPS or Asherson's syndrome) is characterized by multiorgan failure
due to widespread microvascular thrombosis.[28 ] Diagnostic criteria for definite CAPS include at least three new thrombotic organ
manifestations within 1 week and evidence of microvascular thrombosis on organ biopsy.
Patients with CAPS may present with profound thrombocytopenia due to DIC and/or TMA.
Since the disorder is associated with significant morbidity and mortality, an aggressive
multimodal treatment strategy is warranted, including therapeutic anticoagulation
with heparin, corticosteroids, cyclophosphamide, plasma exchange therapy, and high-dose
IVIGs.[29 ] Investigational drugs are rituximab, which targets autoantibody-producing B cells,
and eculizumab, which prevents cleavage activation of complement component 5 (C5).
Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin therapy mediated
by platelet-activating IgG antibodies against the platelet factor 4 (PF4)/heparin
complex.[30 ]
[31 ] The risk of HIT is higher in surgical than in medical patients and after UFH compared
with LMWH exposure. Activation of platelets, monocytes, granulocytes, and endothelial
cells by IgG-PF4/heparin immune complexes through an Fc-dependent mechanism triggers
a vicious cascade of thrombo-inflammatory events, which results in massive intravascular
thrombin generation with an exceedingly high risk for venous, arterial, or microvascular
thrombosis. In classical HIT, platelet-activating IgG antibodies against PF4/heparin
complexes are detectable as soon as 4–5 days after initiation of heparin, with thrombocytopenia
and/or thromboembolic events typically occurring after 5–14 days. The clinicopathological
diagnosis of HIT involves a multistep process: First, in patients with suspected HIT,
pretest clinical probability should be assessed using the 4Ts score ([Table 2 ]). Second, in patients with a 4Ts score greater than 3 or uncertainty regarding the
validity of information required to calculate the score, a screening test for PF4/heparin
or PF4/polyanion antibodies should be ordered. Third, a positive HIT screening test
should be followed by a functional platelet activation test to confirm HIT, for example,
heparin-induced platelet activation (HIPA) test or serotonin release assay (SRA).
Pathophysiologically relevant antibodies show a characteristic reaction pattern, with
no platelet activation in the absence (0 IU/mL) or presence of excess heparin (50–100 IU/mL)
and maximal platelet activation at therapeutic heparin concentrations (0.2–1.0 IU/mL).
Table 2
4Ts score to assess the pretest clinical probability of HIT
Points
Thrombocytopenia
Onset of thrombocytopenia
Thrombosis or other symptoms
Other causes of thrombocytopenia
2
Platelet count decrease > 50% and nadir ≥ 20 × 109 /L
Days 5–10, or day 1 if heparin exposure within previous 30 d
New thrombosis or skin necrosis or acute systemic reaction
None
1
Platelet count decrease 30–50% or nadir 10–19 × 109 /L
> Day 10, or day 1 if heparin exposure within previous 30–100 d
Progressive or recurrent thrombosis or non-necrotizing skin lesions
Possible
0
Platelet count decrease < 30% or nadir < 10 × 109 /L
≤ Day 4 with no recent heparin exposure
None
Definite
Abbreviation: HIT, heparin-induced thrombocytopenia.
Note: Total scores of 0–3, 4–5, and 6–8 indicate a low, intermediate, and high pretest
clinical probability for HIT, respectively.
Source: Adapted from Erkan et al.[28 ]
In patients with either a high pretest clinical probability for HIT (i.e., 4Ts score
≥ 6), a strongly reactive (i.e., optical density > 1.0 units) quantitative PF4/heparin
(polyanion) enzyme immunoassay (EIA) or a positive qualitative PF4/heparin particle
gel immunoassay, or confirmed HIT, heparin should be replaced by therapeutic dosages
of an appropriate alternative anticoagulant, such as danaparoid, argatroban, or fondaparinux.[32 ] Despite profound thrombocytopenia and recent surgery, patients with confirmed HIT
typically lack severe bleeding symptoms, and prophylactic platelet transfusion is
thus not indicated. In HIT patients with overt thrombosis, anticoagulation should
be continued for 3–6 months, depending on the severity of the thromboembolic event,
the presence of residual vein thrombosis or persisting clinical symptoms, and tolerance
of anticoagulant therapy. Provided that platelet counts have stabilized above the
lower limit of the normal reference range, both VKA and DOACs are valid options for
oral maintenance therapy following initial parenteral treatment with non-heparin anticoagulants.
Increasing evidence also exists for the (off-label) use of DOACs in acute HIT.[33 ] The optimal duration of anticoagulation in patients without overt thrombosis is
not clear.[34 ] While some experts deem cessation of anticoagulation acceptable upon platelet count
recovery, others prefer treatment for up to 3 months, considering that HIT-associated
vascular thrombosis might have been clinically obscure. In most patients with HIT,
platelet-activating PF4/heparin IgG antibodies are no longer detectable 3 months after
heparin discontinuation.
Regarding timing of thrombocytopenia relative to heparin initiation, classical HIT
can become manifest as typical-onset HIT (i.e., drop in platelet counts after 5–14
days) or rapid-onset HIT (i.e., drop in platelet counts within 1–2 days), when heparin
exposure within the previous 3 months has resulted in preformed, not yet cleared PF4/heparin
IgG antibodies. In either case, the time course of antibody formation is consistent
with a secondary rather than a primary immune response, with anti-PF4/heparin IgG
occurring as early as 4–5 days after heparin initiation. A potential explanation is
that naturally occurring polyanions such as bacterial lipopolysaccharide, RNA/DNA,
or polyphosphate can also interact with cationic PF4 and mimic HIT antigens, suggesting
that classical HIT represents a misdirected, evolutionarily ancient (antimicrobial)
immune response.[35 ] Likewise, non-heparin polyanionic drugs like hypersulfated chondroitin sulfate or
pentosan polysulfate can trigger “HIT” with characteristic PF4/heparin (polyanion)-dependent
reaction patterns in screening and functional HIT assays, but without proximate heparin
exposure.
Autoimmune HIT and (Spontaneous) HIT Syndromes
In some patients with proximate heparin exposure, PF4/heparin antibodies may develop
to autoantibodies that persist despite cessation of heparin and that are responsible
for autoimmune HIT (aHIT) entities like delayed-onset HIT, persisting (refractory)
HIT, heparin “flush” HIT, or fondaparinux-associated HIT.[35 ] Although antibody formation is initially triggered by heparin or other exogenous
polyanions, the primary antigen in aHIT is PF4 in the (relative) absence of heparin.
In functional assays (HIPA, SRA), aHIT antibodies thus strongly activate platelets
without addition of heparin, albeit endogenously released polyanions may play a role.[35 ]
Over the past decade, HIT-like disorders without proximate heparin exposure have been
described. These include spontaneous HIT syndrome observed in surgical patients following
major orthopedic procedures, such as knee arthroplasty, or in medical patients following
viral or bacterial infections, and, recently, vaccine-induced immune thrombotic thrombocytopenia
(VITT) following active immunization against SARS-CoV-2 with viral vector-based vaccines.[35 ]
[36 ]
[37 ]
[38 ] In these disorders, which are characterized by atypically located thromboses such
as cerebral venous thrombosis and a DIC-like coagulopathy, the primary antigen is
PF4, although pathophysiologically relevant IgG antibodies are also detected by some,
but not all, PF4/heparin (polyanion) EIAs.[39 ] While serum from a subgroup of patients with spontaneous HIT syndrome or VITT shows
platelet activation with buffer, addition of PF4 is typically required to induce a
platelet response.[36 ] Although platelet activation is not further enhanced or even inhibited by heparin,
patients with spontaneous HIT syndrome or VITT should be preferentially treated with
non-heparin anticoagulants. High-dose IVIGs are an option in particularly severe or
refractory cases.[40 ]
[41 ] Similar to isolated HIT, SARS-CoV-2-vaccinated individuals with thrombocytopenia
due to PF4-dependent platelet-activating antibodies may present without clinically
overt thrombosis. In such patients, the term “vaccine-induced prothrombotic immune
thrombocytopenia (VIPIT)” may more adequately describe the hypercoagulable state.
Still, specific and swift treatment with non-heparin anticoagulants and possibly IVIGs
is warranted to prevent catastrophic vascular thrombosis.[42 ]
[43 ] Choice of anticoagulants and duration of anticoagulant therapy in patients with
spontaneous HIT syndrome and VITT/VIPIT are likely similar to those in classical HIT.
Immune Thrombotic Thrombocytopenic Purpura
Immune thrombotic thrombocytopenic purpura (iTTP) is a TMA caused by a severe autoantibody-mediated
deficiency in the von Willebrand factor (VWF)-cleaving metalloproteinase, ADAMTS13.[44 ] Formation of platelet- and VWF-rich microthrombi leads to microangiopathic hemolytic
anemia with the detection of red blood cell (RBC) fragments on peripheral blood smears
and organ impairment (e.g., neurological deficits, heart failure, renal insufficiency).
Treatment of iTTP includes immediate plasma exchange therapy, corticosteroids, and
caplacizumab, a nanobody targeting the GPIb-binding site on the VWF A1 domain.[45 ] Rituximab should be considered in refractory/relapsing iTTP or upfront in cases
with vital organ damage. Although the pathophysiology of iTTP involves microvascular
thrombosis induced by supranormal VWF multimers, routine use of antiplatelet agents
such as ASA or P2Y12 ADP receptor antagonists during the acute phase is not recommended.[46 ] Low-dose ASA may be considered, however, following recovery of platelet counts to
greater than 50 × 109 /L. In iTTP patients with macrovascular thrombosis and an indication for therapeutic-dose
anticoagulation or antiplatelet therapy, the increased risk of bleeding during treatment
with caplacizumab, which impairs VWF-dependent primary hemostasis, must be considered.
Disseminated Intravascular Coagulation
DIC is characterized by systemic activation of the hemostatic system resulting in
diffuse thrombin generation, fibrin deposition, and platelet sequestration.[47 ]
[48 ] Formation of hyaline thrombi in small- and medium-size vessels may lead to organ
dysfunction, while activation of the fibrinolytic system together with platelet and
clotting factor consumption may result in a severe bleeding tendency. DIC is caused
by an underlying disease and can be grouped in four categories according to prevailing
pathophysiological mechanisms and clinical symptoms.[48 ]
Type 1—Bleeding Type (or Hyperfibrinolysis Predominance Type)
This type of DIC is commonly seen in patients with acute promyelocytic leukemia or
vascular causes such as aortic aneurysms. Inadequate (reactive) activation of the
fibrinolytic system leads to increased plasmin generation with a diffuse bleeding
tendency.
Type 2—Organ Failure Type (or Hypercoagulation Predominance Type or Hypofibrinolysis
Type)
This type of DIC is typically observed in patients with bacterial sepsis. The pathophysiology
is multifactorial, involving increased expression and/or secretion of tissue factor,
plasminogen activator inhibitor-1 (PAI-1), DNA, histones, leukocyte proteases (e.g.,
elastase, cathepsin G), and neutrophil extracellular traps (NETs). PAI-1-mediated
impairment of fibrinolysis promotes the formation of microthrombi and organ dysfunction.
Type 3—Massive Bleeding Type (or Consumptive Type)
This type of DIC is caused by massive concomitant activation of procoagulant and fibrinolytic
pathways leading to consumptive coagulopathy and an acute, life-threatening bleeding
tendency. Characteristic causes are major traumatic, surgical, or peripartum hemorrhages
with extensive tissue damage.
Type 4—Nonsymptomatic Type (or Pre-DIC)
This type of DIC is typically observed in patients with solid malignancies. A comparably
weak and more chronic activation of coagulation and fibrinolysis is associated with
no or little symptoms.
Various scoring systems are available to diagnose DIC, one of which is the ISTH/SSC
score for overt DIC.[47 ] This score is based on platelet count (0–2 points), prothrombin time (0–2 points),
plasma fibrinogen (0–1 point), and plasma fibrin generation markers such as soluble
fibrin monomer (SFM) or fibrin degradation products (FDPs, e.g., D-dimer [0–3 points]).
A sum score of ≥5 is compatible with overt DIC.
Patients with DIC type 2 or 4 are at significant risk of VTE, and prophylactic anticoagulation
with LMWH or UFH should thus be considered in the absence of acute bleeding symptoms,
while therapeutic anticoagulation is indicated in patients with overt thrombosis.[48 ] Dose adjustment may be required dependent on platelet count and perceived bleeding
risk. Post hoc subgroup and meta-analyses suggest that antithrombin (AT) substitution
reduces all-cause mortality in patients with septic DIC by 35–40%, with more pronounced
effects in patients not receiving prophylactic anticoagulation.[49 ]
[50 ] However, currently available evidence is not sufficient to promote routine use of
AT concentrates in this clinical scenario. According to the personal opinions of the
authors, substitution of AT may be considered on an individual basis in patients with
sepsis-associated DIC, signs of micro- or macrovascular thrombosis, and significantly
reduced AT plasma levels (i.e., < 30–50%), particularly in those not deemed eligible
for adequate anticoagulation. Still, the increased bleeding risk associated with AT
supplementation must be considered.[49 ] Other drugs introduced to restore the anticoagulant capacity in severe sepsis have
either been withdrawn from the market due to lack of efficacy (recombinant human activated
protein C, drotrecogin alfa [activated]) or have not been approved outside Japan (recombinant
human soluble thrombomodulin, ART-123). Nevertheless, a retrospective analysis of
the PROWESS study suggested that drotrecogin alfa (activated) has a favorable risk–benefit
profile in patients with sepsis and overt DIC,[51 ] supporting the concept that restoration of natural anticoagulants may prove beneficial
in patients with a high risk of multiorgan failure due to widespread microvascular
thrombosis.
Sepsis-induced coagulopathy (SIC) is an entity located upstream of DIC in the continuum
of acquired coagulation abnormalities observed in patients with sepsis and thrombocytopenia.[52 ] While diagnosis of SIC is also based on platelet count and prothrombin time, the
variables plasma fibrinogen and SFM/FDPs are replaced by the SOFA score indicating
organ damage. Compared with patients with overt DIC, patients with SIC have less pronounced
derangement of the hemostatic system and a lower risk of bleeding, warranting more
aggressive antithrombotic strategies to prevent or treat thrombosis despite thrombocytopenia.
Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired pluripotent hematopoietic
stem cell disorder with an incidence of 0.1–0.2 per 100,000 person-years.[53 ] The etiopathogenesis of PNH involves a two-step process. The first step is an acquired
somatic mutation in the phosphatidylinositol glycan class A gene (PIGA ), which leads to loss of glycosylphosphatidylinositol (GPI)-anchored membrane proteins,
such as complement regulatory factors CD55 and CD59. The second step is a cellular
immune reaction against healthy hematopoietic stem cells, which do not carry the PIGA mutation and are thus not deficient in GPI-anchored membrane proteins. T- and natural
killer cell-mediated cytotoxicity results in normal bone marrow failure and expansion
of the PNH clone. Complement-induced damage of CD55- and CD59-deficient erythrocytes
causes hemolytic anemia, hemoglobinuria, and nitric oxide (NO) depletion. In PNH,
the coagulation and complement cascades cooperate with intravascular RBC lysis in
the generation of a highly thrombogenic state with significant risks for venous, arterial,
and microvascular thrombosis.[54 ] Thromboembolic events, renal failure, and pulmonary hypertension have negative impacts
on patient survival. Dysphagia, abdominal pain, erectile dysfunction, and fatigue
contribute to morbidity. Diagnosis is based on flow cytometric detection of the PNH
clone, which can be achieved by analysis of RBC CD55/CD59 expression or leukocyte
binding of fluorescent aerolysin (FLAER), an inactive variant of the bacterially derived
aerolysin with high specificity and affinity for the GPI anchor.[55 ]
In PNH, venous thromboembolic events (80–85%) are more frequent than arterial thromboembolic
events (15–20%).[53 ]
[54 ] Thrombosis occurs at unusual sites (e.g., hepatic/visceral veins, intracranial vessels,
cutaneous microcirculation), precedes PNH diagnosis in 5–10% of patients, and is associated
with the PNH clone size.[56 ] Complement inhibition with C5 monoclonal antibodies, eculizumab or ravulizumab,
is standard of care in all symptomatic PNH patients with a hemolytic phenotype, significantly
reducing the risk of thrombotic events.[57 ] Additional OAC with a VKA or DOAC is indicated in patients with a history of thrombosis
and should be considered as primary thromboprophylaxis in asymptomatic patients not
receiving anti-C5 therapy (e.g., in those with a large PNH clone size and/or additional
risk factors for thrombosis).
In clinical practice, PNH testing is warranted in patients with venous or arterial
thromboembolism meeting at least one of the following criteria:
Signs of hemolysis (elevated lactate dehydrogenase, bilirubin, and reticulocytes;
low haptoglobin).
Thrombosis at unusual sites.
Cytopenia (including low platelet counts).
Recurrence of thrombosis despite appropriate anticoagulation.
