Haematological Flashcards
What Is a Practical Approach to the Patient
Presenting in the Preoperative Clinic
with a History of Apparently Clinically
Significant Coagulation Disorder?
An excellent schema on how to assess such a patient has
been outlined by Harrison et al. [1].
Key facets of the history include the following:
• Clarifying the patient’s definition of what exactly they
mean by a bruise?
• Is the bruising acute or longstanding?
• Do they have photographs of past lesions?
• Have they noticed petechiae or purpura with the bruises?
• Are the bruises spontaneous or associated with trauma?
• Family history of bleeding?
• What is the age of the patient?
• What medications/herbal products is the patient taking?
• What is the diet and state of nutrition of the patient?
• Are there risk factors for liver disease?
The examination should include assessing the following:
• The size, number, and location of bruises
• Signs of poor nutrition – cachexia and brittle hair
• Signs of liver disease – jaundice, hepatomegaly, and ascites
Screening baseline investigations should include the
following:
• CBC, blood smear, coagulation screen, and renal and liver
function tests
The patient should be requested to complete the
International Society on Thrombosis and Hemostasis
Bleeding Assessment Tool (ISTH-BAT). This tool is avail-
able at https://bleedingscore.certe.nl/. The ISTH-BAT
records the presence and severity of bleeding symptoms in
14 situations, e.g., epistaxis, hematuria, and dental extrac-
tion, and has been validated as a useful screening and struc-
tured tool to assist in determining who should undergo
further testing for Von Willebrand disease (VWD), the most
common inherited disorder of coagulation [2]. There is lim-
ited evidence that the ISTH-BAT is abnormal in those with
congenital defects in platelet function [3]. A “normal” ISTH-
BAT cut-off is 3 for males and 5 for females [4].
What Is the Basic Sequence of Events When
the Hemostatic System Is Activated?
Primary hemostasis involves vasospasm at the site of injury,
exposure of subendothelial collagen on vascular disruption,
platelet adhesion mediated by von Willebrand factor (VWF),
and activation and aggregation of platelets leading to plug
development.
Secondary hemostasis occurs simultaneously and involves
activation of the coagulation cascade and subsequent fibrin
clot formation.
How May Bleeding Disorders Be Broadly
Classified?
Primary hemostatic defects – decreased platelet number or
impaired platelet function, and VWF deficiency.
Secondary hemostatic defects – coagulation factor
defects.
What Does the PT and APTT Assess?
The PT and APTT are non-specific tests for secondary hemo-
static defects.
The PT assesses the extrinsic and final common pathway
of the coagulation system.
The extrinsic pathway is initiated by release of tissue fac-
tor (TF), a transmembrane receptor for factor VII/VIIa (FVII/
VIIa). TF is constitutively expressed by subendothelial tissue
but is separated from circulating FVII by an intact endothe-
lium. TF is expressed in relative abundance in the brain,
lung, uterus, testis, and heart [5]. Breach of the endothelium
by trauma or other injury allows TF to initiate immediate
activation of the extrinsic system.
The APTT assesses the intrinsic and final common path-
ways of the coagulation system.
The intrinsic pathway is initiated by trauma within the
vascular system via activated platelets, exposed endothe-
lium, and other initiators. It involves FXII, XI, IX, X, and
VIII among other factors.
How Should Prolonged PT and APTT Results
Be Interpreted?
An excellent approach to this question has been outlined by
Kamal et al. [6].
1. Are the values artifactually elevated?
(a) A high hematocrit reduces the volume of plasma col-
lected resulting in a relative increase in the volume of
citrate anticoagulant in the collecting tube. When the
plasma is added to the clotting test reagents, the
excess citrate causes an artifactual increase in clot-
ting time. This can occur if the hematocrit is >55%.
Advise the laboratory of this condition so the tubes
containing the appropriate calibrated amount of anti-
coagulant can be used.
(b) Plasma turbidity present in lipemic, hemolyzed, or
icteric plasma can interfere with photo-optical clot
systems. Manual visualization of clot formation over-
comes this artifactual error.
2. Is the patient receiving anticoagulants?
(a) Coumadin
(b) Xa and thrombin inhibitors
(c) Heparin (including low molecular weight heparin,
which can prolong the APTT)
(d) Herbal products
3. Is the prolongation due to systemic disease?
(a) Liver
(b) Auto-immune
(c) Disseminated intravascular coagulation (DIC)
(d) Fibrinolysis
(e) Other
A reasonable approach, in the absence of the above, is to
repeat the tests and request a mixing study. If the pro-
longed values are confirmed, the mixing study helps
assess if the patient has a factor deficiency or has a factor-
inhibiting antibody. It is very helpful in determining the
next steps in assessing the exact cause of the coagulation
abnormality.
What Is a Mixing Study?
The test involves mixing an equal volume of the patient’s
plasma with pooled normal plasma and repeating the PT and
APTT immediately.
Correction of the values to normal is suggestive of a fac-
tor deficiency.
No correction or partial correction suggests the presence
of a coagulation inhibitor.
Who Should Have Surgery Deferred and/or
Be Referred to a Hematologist for Further
Evaluation and Management?
- Abnormal coagulation studies warrant further investiga-
tion and/or referral if not readily explainable based on
coexisting disease, medication use, known presence of an
inhibitor, or past history. - Any individual who appears to have a previously undiag-
nosed clinically significant bleeding disorder should be
investigated prior to surgery. Using the ISTH-BAT can be
helpful in making this decision. - Concerning findings on history and especially physical
examination, even in the absence of definitive laboratory
findings, should prompt postponement and referral for
specialist evaluation.
What Can Cause Isolated APTT Prolongation But Is Not Associated with Bleeding?
○ The APTT test involves the addition, among other substances, of phospholipid to the plasma sample of the patient.
○ The presence of lupus anticoagulant (LAC), an antiphospholipid antibody, in the sample will interfere with the added phospholipid and cause prolongation of the APTT (act as an inhibitor).
- No correction or partial correction of values is seen when a mixing study is performed.
- Patients who have LAC antibodies are at increased risk of thrombosis, as they bind to endothelial cells, monocytes, and platelets and can cause activation of the coagulation system.
What Condition Causes Easy Dermal Bruising in the Elderly in the Face of Normal Coagulation Studies?
Older individuals are susceptible to actinic purpura, a condition that arises secondary to loss of collagen, thinning of the dermis, and reduced connective tissue support for vessels and capillaries. This form of bruising is commonly seen on the dorsum of the hands and extensor areas of the hands and
shins. It is benign and usually resolves within 3 weeks of a traumatic event.
How Common and Concerning Is Easy
Bruising Preoperatively?
“Easy bruising” and other events suggestive of a bleeding
disorder (epistaxis, menorrhagia, bleeding after tooth extrac-
tion or surgery) are commonly reported, and any one of these
events may occur in >25% of the general population [7].
Screening for bleeding disorders prior to surgery using a
bleeding assessment tool (BAT) is recommended by the
European Society of Anesthesiology with referral to a hema-
tologist if any inherited bleeding disorders are suspected [8].
Vries et al. [9] screened over 35,000 patients with a BAT-
like questionnaire over 3 years at a single site and uncovered
many patients reporting bleeding symptoms (≈10% of the
sample). In the small subset of this group who underwent
comprehensive coagulation testing, including factor assays
and platelet function analysis, minor hemostatic abnormali-
ties were detected in 8.8%, a value less than that noted in the
group denying bleeding symptoms (10.5%). Only one patient
in the “bleeding symptoms” group was referred to a hema-
tologist, as there was concern that the patient had clinically
significant bleeding.
From these data, we can conclude that “easy bruising” is
very commonly reported and of doubtful, if any, clinical sig-
nificance. Nevertheless, as the case described demonstrates,
there are occasional circumstances where “easy bruising” is
indicative of a serious underlying abnormality. In the vast
majority of cases, elimination of a significant cause can be
achieved from history alone obviating the need for extensive
workup.
True/False Questions
1. Which of the following results in a prolonged APTT?
(a) Factor VIII deficiency
(b) Lupus anticoagulant positive plasma
(c) Xa inhibitor medications
(d) Platelet dysfunction
(e) Disseminated intravascular coagulation
1a.T
1b.T
1c.T
1d.F
1e.T
- “Easy bruising” reported by a patient is a condition
(a) where a BAT-like questionnaire is helpful
(b) where a VIII assay is helpful
(c) that is usually benign
(d) commonly associated with abnormal coagulation
studies
(e) where lupus anticoagulant is usually positive
2a.T
2b.F
2c.T
2d.F
2e.F
What Is Thrombocytopenia?
An individual with a platelet count of <150 × 109/L is con-
sidered thrombocytopenic.
How Should an Incidental Preoperative Finding of Recent Onset (<3 Months) Thrombocytopenia Be Approached?
○ A rational approach to the incidental finding of recent-onset thrombocytopenia has been outlined by Bradbury and Murray [1].
○ An unexpected low platelet count should be confirmed by a repeat CBC and trigger an assessment of a blood smear to exclude clumping or the presence of giant platelets.
○ Outside a surgical setting, individuals with platelet counts of 100–150 × 109/L without features suggestive of systemic disease may be subject to observation and follow-up with another CBC in 6 weeks. It would seem reasonable in the preoperative setting to follow a similar approach if the procedure is scheduled in the immediate future. Inform the patient,
document the finding, and proceed with surgery.
For individuals with recent-onset incidental thrombocytopenia with platelet counts <100 × 109/L or with undiagnosed thrombocytopenia associated with anemia or neutropenia, postponing surgery pending review of the patient by a hematologist is warranted.
Urgent referral is indicated in a patient with recent-onset incidental thrombocytopenia and a platelet count ≤50,000 × 109/L. An emergent referral should take place if, in addition, signs of petechia or bruising are present, or the patient presents with active bleeding.
What Are the Common Causes
of Thrombocytopenia?
Thrombocytopenia occurs because of impaired production,
increased destruction/consumption, or abnormal distribution
of platelets, or a combination of these factors [1, 2].
Common causes of impaired production include bone
marrow failure or suppression, recent chemotherapy, infec-
tion, nutritional deficiencies (B12 and folate), congenital con-
ditions, myelodysplastic syndrome, and neoplastic bone
marrow infiltration.
Increased destruction/consumption states include sepsis,
autoimmune syndromes (e.g., systemic lupus erythematosus,
sarcoid), drug-induced (e.g., quinine, NSAIDs), heparin-
induced, immune mediated purpura, mechanical (mechani-
cal heart valves or extracorporeal support devices),
disseminated intravascular coagulation (DIC), and
preeclampsia.
Sequestration/combination factors include chronic alco-
hol intake, liver disease, pulmonary emboli, portal hyperten-
sion, splenomegaly, and dilutional states.
Isolated thrombocytopenia in an asymptomatic patient
with a normal blood smear in the absence of factors such as
those listed above is usually ITP. It is a diagnosis of exclu-
sion and can occur at any stage of life, including childhood.
Dysplastic causes are more common in older patients.
Dysplasia is not always malignant but may proceed to malig-
nancy. Bruising, petechia, and bleeding episodes in associa-
tion with thrombocytopenia are concerning, as are symptoms
of night sweats, fevers, and weight loss, which suggest a
malignant cause. Any form of cancer may be associated with
thrombocytopenia.
Thrombocytopenia may indicate the presence of HIV,
hepatitis, or other still occult infection.
Drug-induced thrombocytopenia is relatively common
[3]. Typically, this occurs within 1 week of drug initiation
and will resolve within a week of stopping the implicated
medication.
Drugs used in the perioperative period such as vancomy-
cin and piperacillin are well-recognized triggers of drug-
induced thrombocytopenia. Anesthetic agents have not been
found to cause thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) should always
be considered in those who have recently been hospitalized
or undergone invasive investigations. HIT occurs as a conse-
quence of the development of antibodies to complexes of
heparin and platelet factor 4 (PF4).
PF4 is a positively charged platelet protein released when
platelets are activated. PF4 inhibits endothelial antithrombin,
thereby promoting thrombosis.
Administered therapeutic heparin displaces PF4 from its
endothelial binding sites and forms immunogenic PF4/hepa-
rin complexes. Development of HIT antibodies in response
to heparin infusions is not uncommon (up to 50% of patients
develop them following cardiopulmonary bypass) [4].
Only a small percentage of those exposed to heparin suf-
fer the clinical features of HIT, thrombocytopenia, and
thrombosis occurring in temporal association with heparin
administration.
The thrombocytopenia usually occurs within 5–14 days
after the provoking heparin dose. If heparin-PF4 antibodies
are already present in the circulation (heparin exposure in the
last 100 days in susceptible individuals), rapid-onset HIT
can occur and thrombocytopenia may become apparent with
24 hours of the new provoking heparin dose.
Unfractionated heparin is more immunogenic than low
molecular weight heparin.
Chronic alcohol intake is associated with thrombocytope-
nia, but platelet values are usually >50 × 109/L; with cessa-
tion, values rebound rapidly (within days).
Thrombocytopenia is a relatively early indicator of portal
hypertension.
What Is the Usual Course of ITP?
ITP results from a combination of the development of anti-
platelet antibodies, impaired megakaryocytopoiesis, and
T-cell destruction of platelets [5]. Newly diagnosed ITP is treated with steroids. Prednisone 1 mg/kg for 2–4 weeks was
the standard therapy, but recent studies suggest that high-
dose dexamethasone pulse treatment may be a more effective
approach [6]. Relapse is common despite steroid therapy,
and in these circumstances rituximab and intravenous
immune globulin (IVIg) are treatment options. Continued
relapse calls for second-line therapy—it is in these circum-
stances that splenectomy is considered, as this procedure has
a long-term complete restoration of normal platelet values of
~70%. An alternative option now available is chronic treat-
ment with a thrombopoietin receptor agonist (TPO-RA).
Romiplostim and eltrombopag are TPO-RAs currently
approved by the US Food and Drug Administration (FDA)
for management of chronic ITP. Studies are lacking on the
efficacy and long-term effects of these agents [5].
Platelet Counts and Neuraxial Anesthesia—
Is There a Consensus on What Are “Safe”
Values?
A recent combined guideline from the Association of
Anaesthetists of Great Britain & Ireland, The Obstetric
Anaesthetists’ Association, and Regional Anesthesia UK
provides some nuanced suggestions about the management
of neuraxial block in obstetric patients with low platelet
counts arising as a consequence of pre-eclampsia and ITP
[7]. On a continuum of risk ranging from normal through
increased, high, and very high, their assessment is seen in
Table 38.1.
A report from the Multicenter Perioperative Outcomes
Group in the United States, using their national database
from 14 major medical centers, assessed the risk of epidural
hematoma in parturients undergoing neuraxial anesthesia
and analgesia [8]. They identified 573 patients with a platelet
count of <100 × 109/L who had epidural or spinal anesthesia.
The risk of hematoma was 11%, 3%, and 0.2% in those with
counts ≤49 × 109/L, 50–69 × 109/L, and 70–100 × 109/L,
respectively. The authors caution that there are insufficient
data to have confidence in the risk estimates for platelet
counts <70 × 109/L. The evidence on this topic is poor. It
seems clear that the risk of hematoma development after
lumbar puncture or neuraxial block in the thrombocytopenic
patient is influenced by the underlying etiology of the throm-
bocytopenic state. Definitive guidance awaits further large
population-based studies.
When Is Prophylactic Platelet Transfusion
Prior to Surgery Appropriate
in the Thrombocytopenic Patient?
There are no robust data to support the practice of prophylac-
tic platelet transfusion except in the setting of acute leukemia
[9]. There is emerging evidence that prophylactic platelet
transfusions are of little value in reducing transfusion rates
and bleeding complications prior to surgery or other invasive
procedures [10, 11]. A reasonable approach would be to
ensure platelets are readily available, if required, in patients
with platelet counts ≤50 × 109/L scheduled to undergo a
major surgical procedure.
How Does the Platelet Count Relate to Bleeding Risk?
○ The platelet count is a relatively imprecise indicator of bleeding risk unless the count is very low.
-Recent data from a study of oncology patients receiving chemotherapy found that counts ≤5 × 109/L were a hallmark of great hemorrhagic
risk relative to those with counts ≥81 × 109/L [12].
○ Patients with platelet counts >50 × 109/L are usually asymptomatic.
○ Those with counts ≤30 × 109/L are susceptible to trauma-induced bleeding, while patients with counts <10 × 109/L are at risk of “spontaneous” bleeding, may have petechiae, present with epistaxis or a major organ-related
bleeding episode.
True/False Questions
1. Thrombocytopenia
(a) is not present if the platelet count is ≤125 × 109/L
(b) is common in sepsis
(c) can arise as a consequence of the use of NSAIDs
(d) is a relatively common finding in patients with alco-
hol use disorder
(e) may be an indicator of portal hypertension
- ITP
(a) occurs because of activation of platelet factor 4
(b) is frequently associated with heparin administration
(c) does not recur once successfully treated
(d) can present as a medical emergency
(e) splenectomy can be a very effective intervention
What Potential Complications Is the Patient
with a History of Venous Thromboembolism
(VTE) Subject to in the Perioperative Period?
Depending on whether long-term anticoagulation is tempo-
rarily held over the perioperative period or continued, the
main risks relate to VTE and bleeding. The likelihood of
either occurrence must be evaluated for each patient and sur-
gical procedure. On the basis of this evaluation, anticoagula-
tion will be continued or held. If held, a further decision is
required regarding the implementation of bridging therapy
and timing of re-introduction of long-term anticoagulation
after surgery
What Are the Main Risk Factors
for Development of Perioperative
Thromboembolism?
The three principal predisposing factors are atrial fibrillation,
presence of a mechanical heart valve, and previous VTE. In
the United States, over six million patients with one or more
of these conditions take long-term thromboprophylaxis
[1, 2]. Other predisposing factors for which patients may
be on long-term anticoagulation therapy include hereditary
thrombophilia (e.g., protein C and protein S deficiency) and
certain specific causes of cerebrovascular and peripheral
arterial disease.
How Is the Thromboembolic Risk Associated with Atrial Fibrillation Estimated?
○ This is determined by whether or not the atrial fibrillation (AF) is valvular in nature.
○ Valvular AF refers to patients in AF with moderate to severe mitral stenosis or a mechanical mitral valve prosthesis.
○ The further increase in risk of VTE (in addition to that arising from AF) in the patient with mitral stenosis or a mechanical heart valve results from conditions of low flow in the left atrium in the case of mitral stenosis and the thrombophilic properties of mechanical heart valves.
○ Valvular AF is considered an indication for long-term anticoagulation with warfarin.
-Patients with moderate to severe mitral stenosis and AF have been largely excluded from randomized controlled trials on the efficacy and safety
of direct oral anticoagulants (DOACs) for long-term anti-coagulation.
- Subsequently, there is insufficient evidence at this time to treat these patients with DOACs.
-DOACs are contraindicated in patients with mechanical heart valves.
-This recommendation is based on the observed increase in ischemic stroke rate and bleeding complications in patients receiving dabigatran compared with warfarin in the RE-ALIGN trial
○ Non-valvular AF, the most common medical indication for chronic anticoagulation, occurs in the absence of moderate to severe mitral stenosis or a mechanical heart valve [3].
- Non-valvular AF can occur in the presence of other valvular disorders (e.g., mitral regurgitation, aortic stenosis).
- Thromboembolic risk for the non-valvular AF patient is calculated using the CHA2DS2-Vasc score [6].
○ A CHA2DS2-Vasc score of 2 or more in men and 3 or more in women requires oral anticoagulation.
