Haematology Flashcards
What percentage of cases of neutropenia are suspected to be drug induced?
70%
What are some of the main culprit drugs responsible for drug-induced neutropenia?
Antibiotics - Chloramphenicol, Dapsone, Isoniazid, Meropenem, Streptomycin, Sulfamethoxazole-trimethoprim
Antifungals - Terbinafine
Antimalarials - chloroquine, primiquine, quinine
Anti-inflammatories - diclofenac, ibuprofen, sulfasalazine
Anti-thyroid drugs - carbimazole, PTU
Antipsychotic drugs - chlorpromazine, clozapine
Antidepressants - mirtazapine, mianserin, tricyclics
Anti-epileptics - Carbamazepine, Ethosuximide, Phenytoin, Valproate, Zonisamide
Cardiovascular drugs - ACEIs, Acetazolamide, Digoxin, Flecainide, Procainamide, Propranolol, Spironolactone, Ticlopidine
Immunomodulators - hydroxychloroquine, leflunomide, rituximab
Others:
Colchicine
Deferiprone
Metoclopramide
Nitrous oxide
Pirfenidone
Chemotherapy-induced neutropenia is often dose-dependent, associated with other cell lines (due to bone marrow toxicity) with the nadir occurring at 7-14 days and recovery over 3-4 weeks - what is unusual about the neutropenia that can occur in patients treated with chemotherapy + Rituximab therapy?
Patients who receive the anti-CD20 monoclonal antibody rituximab in addition to chemotherapy may, rarely, experience a delayed neutropenia beyond this 3-4-week period with unpredictable onset and recovery time
Why is it important to differentiate between idiosyncratic drug-induced neutropenia and dose-dependent drug-induced neutropenia?
Because idiosyncratic drug-induced neutropenia is associated with increased rates of infection and mortality rates ranging from 2.5-25%
How do you treat drug-induced neutropenia?
Cease the culprit medication immediately in patients with evolving neutropenia or agranulocytosis. However, if the effect is dose-dependent and mild, drugs can sometimes be continued with close monitoring, although making this distinction can be difficult
What are the most common infectious-causes of neutropenia?
Viral infections
Short and self-limited:
Viral hepatitis
Viral exanthems (measles, rubella, varicella)
Influenza
Cytomegalovirus
Parvovirus
Prolonged:
HIV
EBV
Can neutropenia be secondary to bacterial infection and if so, which ones in particular?
Brucellosis
Mycobacterial infections incl TB
Rickettsial infections
Malaria
Severe overwhelming sepsis - poor prognostic indicator
How do you make the diagnosis of autoimmune neutropenia (ie related to autoimmune disease such as RA/SLE)
Largely clinical - as assays for antineutrophil autoantibodies are difficult to perform and generally considered to be unreliable or non-diagnostic
What is the significance of autoimmune neutropenia?
Neutropenia can be triggered by a flare in the underlying disease and tends to track disease activity.
How do you treat autoimmune neutropenia?
Most cases improve on management of the underlying condition and rarely require specific treatment
What is the classic triad of Felty’s syndrome?
RA + neutropenia + splenomegaly
What is the significance of recognising Felty’s syndrome?
Neutropenia tends to be severe and is associated with significant morbidity from infective complications and the RA is severe and deforming.
How do you treat Felty’s syndrome?
Felty’s syndrome is currently rarely seen because of early and aggressive management as well as substantial advancements in the efficacy of available therapies
Controlling the RA tends to resolve the neutropenia, but G-CSF (filgrastim or pegylated filgrastim) may be necessary in refractory cases
What nutritional deficiencies can cause neutropenia?
Vitamin B12 (assoc macrocytic anaemia)
Folate (assoc macrocytic anaemia)
Copper
Global - anorexia nervosa
What features may suggest a bone marrow failure/infiltration/dysplasia as cause of neutropenia?
- Other cell lines affected (eg anaemia)
- B symptoms incl fevers, weight loss, night sweats
- lymphadenopathy or bone pain
- blood film abnormalities incl blasts or in solid organ malignancies assoc with marrow involvement -> leukoerythroblastic anaemia (that is, nucleated red cells and neutrophil precursors)
What features does T-cell large granular lymphocytic leukaemia (T-LGLL)-associated neutropenia share with Felty’s syndrome?
An association with RA
Splenomegaly
Severe neutropenia
An association with HLA-DR4.
How do you differentiate T-cell large granular lymphocytic leukaemia (T-LGLL)-associated neutropenia from Felty’s syndrome?
Monoclonal lymphocytes in T-LGLL
vs
Oligoclonal or polyclonal lymphocytes in Felty’s syndrome
How do you diagnose Chronic Idiopathic Neutropenia?
Once you have excluded other causes eg with history and exam + bone marrow biopsy
More common in px with mediterranean ancestry + mild-to-mod neutropenia (rarely dips <0.8 or requires treatment)
What is constitutional neutropenia (previously called benign ethnic neutropenia)?
A form of chronic, mild neutropenia in patients of the relevant ethnicity, with no other evident causes
Ethnicities - some Mediterranean, African, Yemenite Jewish, Ethiopian, Middle Eastern, Caribbean and West Indian populations
The diagnosis requires at least three blood tests showing neutropenia at least two weeks apart + exclusion of other causes
Note no associated increased rates of infection
What are the core features of cyclic neutropenia (CN)?
Cyclic neutropenia (CN) is a rare condition characterised by self-limiting neutropenia associated with fever, skin or oral ulcers, and/or cervical lymphadenopathy during a neutrophil nadir that occurs every 2-5 weeks
Patients are generally well between episodes
The absolute neutrophil count oscillates and severe neutropenia typically lasts 4-5 days each cycle, during which patients are also prone to infections
Cycle lengths vary between patients but are consistent in an individual
To diagnose CN, serial FBCs are required 2-3 times a week for at least six weeks to establish the pattern of neutropenia
The diagnosis can be confirmed with genetic testing for ELANE gene mutations and does not routinely require a bone marrow biopsy.
CN is an autosomal dominant condition resulting from mutations in the ELANE gene, the same gene implicated in many cases of SCN
What initial investigations should be ordered for a patient with neutropenia?
Recommended for all patients:
- FBC with differential.
- Blood film.
- EUC.
- LFTs.
Focused investigations based on clinical assessment:
- Septic screen (including blood culture).
- ANA, dsDNA, RF, anti-CCP, ESR/CRP.
- Flow cytometry
- B12/folate/copper
- HIV, HCV, HBsAg, HBsAb, HBcAb and other viral serology as appropriate.
Specialised investigations considered by a haematologist:
- Bone marrow biopsy.
- Genetic studies.
What are the main risks with G-CSF (Filgrastim) therapy
bone pain, myalgias, splenomegaly and osteoporosis
There is also a theoretical increased risk for AML in Severe Congenital Neutropenia
G-CSF is safe in acquired causes of neutropenia with no identified increased risk for AML
What are the indications for considering bone marrow transplant in a patient with Cyclic Neutropenia?
Disease refractory to G-CSF, recurrent severe infections, bone marrow failure and malignant transformation
What is the most common inherited bleeding disorder?
Von Willebrand Disease
What is the mode of inheritance for von Willebrand disease?
Autosomal with variable penetrance and expressivity
What is the cause and pathophysiology of von Willebrand Disease?
VWD is due to qualitative and quantitative defects in von willebrand factor secondary to an autosomal genetic condition
Rarely patients can develop acquired von Willebrand syndrome secondary to lymphoproliferative disorders (e.g. MGUS, MM, Waldenstrom’s) and has been reported with aortic stenosis and hypothyroidism
Von Willebrand Factor is synthesised in endothelial cells and megakaryocytes and is a high molecular weight multimer
VWF mediates platelet adhesion to exposed subendothelium at sites of vascular injury + stabilises and carries factor VIII (protective co-factor)
Patients with vWD predominantly have symptoms of platelet dysfunction eg mucosal bleeding
Type 1 = quantititive defect
Type 2 = qualitative defect
Type 3 = severe quantitative defect
What subtypes of von Willebrand disease may be accompanied by haemarthroses and low factor VIII levels?
Type 2N and type 3 - can resemble haemophilia A
Type 2N = marked decrease in the affinity of vWF for factorVIII thus patient’s factor VIII half life is very short (plasma levels reduced to 5-25%)
Type 3 = complete absence of VWF
What is unique about Type 2B von Willebrand Disease?
It is actually a result of a gain-of-function mutation which increases binding of vWF to platelets resulting in the platelet-VWF complex being more readily cleaved by ADAMTS13 and subsequently cleared by the reticuloendothelial system
These patients often have a mild-to-moderate thrombocytopenia
What blood group has lower von Willebrand Factor levels at baseline?
O-type blood
Why might a young adult with mucosal bleeding who is diagnosed with von Willebrand’s disease have normal von Willebrand Factor levels in later life?
Because von Willebrand Factor levels increase with age and may, in a sizeable % of patients reach normal levels later in life
Note vWF levels can increase with exercise, inflammation, stress and menstrual cycle/pregnancy
What are the typical symptoms of von Willebrand Disease?
Easy bruising
Excessive bleeding from minor wounds/surgery esp mucosal eg tonsillectomy, wisdom tooth extraction
Mucosal bleeding
Menorrhagia
May have symptoms of iron deficiency/anaemia
Which subtypes of VWD are associated with more severe disease?
Type 2 or 3 - symptoms may begin at earlier age, more likely to have positive family history (as autosomal dominant) and in cases of type 2N or 3 may have haemarthroses
How do you test for von Willebrand Disease?
In addition to FBC and coagulation tests (which are often normal) request:
1) von Willebrand factor antigen
(measures the quantity of plasma vWF using ELISA-based method; <30% = VWD, 30-50% with positive bleeding history also indicates VWB)
2) Platelet-dependent VWF activity (eg VWF:RCo or VWF:GP1BM or VWF:CB)
- these assess the ability of VWF to bind to its normal binding partners
VWF:RCo has been the gold standard but not automated and not as sensitive so VWF:GP1bM/collagen so now others mostly used
<30IU = VWD
30-50IU and bleeding history = VWF
3 ) Factor VIII levels
(often normal or low-normal but may be frankly decreased in VWD Type 2N or 3)
How do you distinguish between VWD and mild haemophilia?
Clinically similar bleeding symptoms although VWD tends to have more mucosal bleeding
Family history - VWD is autosomal whilst haemophilia is X-linked pattern
Investigations:
haemophilia have reduced Factor VIII with normal VWF Ag and activity
Type 3 VWD - factor VIII + VWF ag + VWF activity all reduced
Type 2N VWD - Use special VWF binding to normal factor VIII studies and/or genetic analysis of the VWF binding site for factor VIII
How do you distinguish the subtype of VWD?
Initially can look at platelet-dependent VWF activity to VWF antigen level
- if ratio >0.7 = Type 1
- if ratio <0.7 = Type 2 because it demonstrates platelet-dependent VWF activity is out of proportion to reduction of VWF in circulation
Can also perform FactorVIII activity to VWF antigen (low in Type 2N)
Can also perform VWF multimer analysis (visually quantifies the densitometry of the bands to distinguish those with large multimers from others
What other tests might you consider in patient with newly diagnosed von Willebrand Disease?
TSH - to detect hypothyroidism
Serum protein electrophoresis - to detect MGUS/MM
How do you treat von Willebrand disease?
Depends on subtype
Note if life-threatening bleeding - treat as for type 3 until more information required with:
VWF-containing concentrate +/- platelet transfusion +/- cryoprecipitate
Type 1
- see whether they respond to desmopressin (desmopressin results in release of vWF and Factor VIII from endothelial stores); patients show have at least 3-5x increase in levels of these 30-60mins post administration
- antifibronolytics (e.g. tranexamic acid)
+ desmopressin (if desmopressin responder)
OR vWF-containing concentrate (if non-responder)
Type 2
- can use desmopressin for 2A and 2M (may respond)
+ antifibrolytic
+ VWF containing concentrates
- however desmopressin ineffective in 2B (and may worsen thrombocytopenia) and 2N
Type 3
- VWF-containing concentrates (note important to give high-purity concentrate which also contains Factor VIII as otherwise takes 6-8hrs post-VWF alone for endogenous levels of Factor VIII to reach haemostatic levels
+
antifibrinolytic therapy
How do you treat patients with chronic or recurrent menorrhagia in setting of vWD?
Hormonal therapy (if benefits > risks) as oestrogen increases VWF and may reduce menstrual blood flow
+
antifibrinolytics
Can consider desmopressin but evidence inconclusive
How do you treat patients with chronic or recurrent or treatment refractory bleeding and VWD?
Prophylactic VWF-containing concentrates + haematologist care
However note some patients can develop antibodies to VWF after treatment with VWF so you need to monitor levels if repeated administration + ensure factor VIII levels are not excessively elevated due to potential risk of thrombosis
What key long-term management issues do you have to consider in patients with VWD?
1) May require intermittent acute treatment for active bleeding throughout their lives
2) May require prophylactic treatment before procedures throughout their lives
3) If become pregnant require high-risk obstetric and haematology care as higher risk incl for delayed/post-natal haemorrhage
4) Can develop antibodies to VWF after repeated administration of VWF-concentrates which reduces effectiveness of VWF-concentrates
What is the mode of inheritance for Haemophilia?
X-linked pattern therefore occurs almost exclusively in males
Haemophilia A is due to deficiency of which coagulation factor?
Factor VIII
Haemophilia B results from the deficiency of which coagulation factor?
Factor IX (9)
Are there any other forms of haemophilia?
Yes - there is an acquired/non-inherited haemophilia which is autoimmune-related
Why might some women manifest with haemophilia-range clotting factors/bleeding symptoms?
Due to lyonisation (random inactivation of the normal X chromosome) or homozygosity or mosaicism or Turner syndrome
What is the pathophysiology of haemophilia?
Genetic defects result in decreased or absent levels of coagulation factor 8 (Haemophilia A) or 9 (Haemophilia B). These are crucial for thrombin generation via the intrinsic pathway. Reduced thrombin generation leads to delayed and unstable clot formation that can be easily dislodged causing excessive bleeding.
What is the hallmark form of bleeding in haemophilia?
Musculoskeletal bleeding
When are patients typically diagnosed with haemophilia?
As children however some, particularly those with mild or even moderate haemophilia who have had no significant haemostatic challenges in their lives may go undiagnosed until adulthood.
Acquired haemophilia is often not recognised or mistake for other acquired bleeding disorders
How do you distinguish haemophilia A from haemophilia B?
The are indistinguishable clinically
Therefore the only way is on plasma factor VIII and IX assay
How do you grade haemophilia?
Into mild, moderate and severe based on factor level
<0.01 = severe
0.01-0.05 = moderate
0.05-0.40 = mild
What is the effect of emicizumab therapy on APTT/factor VIII levels in patients with haemophilia A?
It will shorten APTT and improve Factor VIII levels - this effect will persist for up to 6 months after discontinuation
Note - in the rare case when the development of anti-emicizumab antibodies is suspected, APTT will be inappropriately prolonged (as emicizumab effect is absent)
What testing should you order in patients with suspected haemophilia?
1) APTT
- typically prolonged (but may not be in mild cases)
- typically corrects with mixing
- if clinical suspicion or prolonged APTT then order
2) Factor VIII and Factor IX assay
3) FBC
- usually normal, may have anaemia if severe bleeding
4) PT
- should be normal
- if prolonged need to check factor VII and factor V
5) von Willebrand factor assay
- to exclude VWD
6) LFTs
- to evaluate for liver dysfunction as cause of prolonged PT/aPTT
What does correction of aPTT with mixing study suggest?
A mixing study involves incubating patient plasma with normal plasma for 2 hours at 37deg and repeat aPTT
If aPTT corrects with a mixing study it suggests a coagulation factor deficiency
If aPTT does not correct it suggests the presence or a coagulation inhibitor
If aPTT is prolonged (and correct on mixing studies) but factor VIII and factor IX levels are normal, what should you test for?
Factor XI and XII levels
What are the key principles of (congenital) haemophilia care?
1) Treatment and prevention of bleeding
2) Rehabilitation after joint and muscle bleeds
3) Prevention and long-term management of joint and muscle damage
- incl physiotherapy, joint protection, maintenance of ROM, balance
4) Education
5) Pain management
6) Dental care
7) QOL and psychosocial support
8) Gentetic counselling and diagnosis
‘
What is meant by haemophilia patients having an aura?
Some patients may experience tingling sensation or tightness within the joint the preceeds the appearance of clinical signs of a joint bleed or recognise early signs before obvious bleedinge
In patients with haemophilia B, the development of inhibitors is often heralded by what?
Anaphylaxis to factor IX products
Thus important to administer in appropriate setting in first 10-20 factor IX exposure days
Those who develop anaphylaxis have an increased risk of developing nephrotic syndrome upon factor IX exposure
How do you treat acute bleeding in congenital haemophilia (in those without factor inhibitors)?
Factor VIII (Haemophilia A) or factor IX (haemophilia B) concentrate infusion
+
Antifibrinolytics (eg tranexamic acid)
+ pain medications
+ consider desmopressin (in patients with mild haemophilia A and demonstrated positive response to desmopressin)
+ topical haemostatic agents eg fibrin sealant
+ PRICE (protection, rest, ice, compression, elevation)
How many haemophilia patients develop inhibitors to infused factor concentrates and how do you manage these patients when they present with acute bleeding?
30% of patients with haemophilia A
5% of patients with haemophilia B
Treatment in these patients is complex and should be managed in a specialist haemophilia center. Depends on current and historical maximum inhibitor titre (determined by <5 Bethesda unit [low-responder inhibitor] vs >5 [high-responder]
Options include:
1) Specific replacement factor at a much higher dose than usual
2) Bypassing agent such as recombinant factor VIIa
(MOA: binds activated factor VII to tissue factor which activates factor X and leads to thrombin generation + at supraphysiological concentrations binds the surface of activated platelets activating factor X independent of tissue factor and generating thrombin)
OR
Factor VIII inhibitor bypassing fraction - contains variable amounts of vit=K dependent clotting factors which generate thrombin by bypassing factor VIII/factor XI in coagulation cascade)
However, there is a risk of risk of thrombotic microangiopathy and thrombosis with the use of these - especially in those patients on emicizumab therapy (avoid for up to 6 months after) or with concurrent antifibrinolytic therapy (so don’t give)
What are the risk factors for development of factor inhibitors in haemophilia patients?
Disease severity - more common in severe haemophilia
Environmental - more common early in factor concentrate treatment, ethnicity (higher in african populations), and varies with infection, age, type of production
Genetic mutation - people with family history or those with mutations that result in absence of a gene product (e.g. large deletions, nonsense mutations) more likely
What are the contraindications to antifibrinolytic agents (e.g. TXA)?
Any haematuria (as unlysed clots will behave like stones causing obstructive nephropathy)
Bleeding into the thoracic cavity - an unlysed haematoma may interfere with respiration
What treatment may be indicated in haemophilia patients with recurrent bleeds into a target joint?
Radioactive synovectomy (synovioorthesis)
- if this fails, may require surgical synovectomy
What are the indications and agents for prophylaxis in haemophilia patients?
Severe haemophilia A or B (including those with inhibitors) + those with mild-to-moderate haemophilia with a severe phenotype
Primary prophylaxis = when started before age 3 / before clinically detectable joint damage
Secondary prophylaxis = therapy initiated after 2 or more joint bleeds but before the onset of joint disease
Tertiary prophylaxis = therapy started after development of joint disease
Agents:
Haemophilia A - factor VIII concentrates OR emicizumab
Haemophilia B - factor IX concentrate
What is the role of Emicizumab in haemophilia A treatment?
Prophylaxis only in haemophilia A patients with or without inhibitors
Cannot be used to treat acute bleeds, cover surgical procedures or haemophilia B prophylaxis
How do you treat haemophilia patients with factor inhibitors?
Goal is to eliminate the inhibitor with the use of Immune Tolerance Induction (ITI)
This involves high doses of relevant factor concentrate for months to years (usually once a day)
If this doesn’t work - can try rituximab
If you come across a patient with haemophilia who was commenced on treatment in the 1970s, what else do you have to be conscious of?
That they may have contracted HCV / HBV or HIV from blood products
70-90% of those treated in 1970s-80s contracted blood-borne diseases (ie before certain measures were instituted)
What are more common - Group 1 or Group 2 inherited thrombophilias?
Group 2 eg factor V Leiden, prothrombin gene mutation and sickle cell disease
Group 1 = reduced level of inhibitors of coagulation cascade
Group 2 = increased levels/function of coagulation factors
What are the 5 types of Group 1 inherited thrombophilias?
1) Antithrombin deficiency
2) Protein C deficiency
3) Protein S deficiency
4) Plasminogen deficiency
5) Dysfibrinolysis
What is the role of antithrombin in coagulation?
AT is a major inhibitor of blood coagulation (ie a natural anticoagulant) - it works by inhibiting the coagulation proteases 2a (thrombin), 10a, 9a and 11a.
Following the administration of heparin or fondaparinux, AT activity is accelerated dramatically due to conformational change induced by heparin binding that exposes the reactive center in AT converting AT from a slow inactivator of coagulation factors to a rapid inactivator (1000-fold increase in AT activity)
Endogenous heparin sulfates in endothelium likely provide this role in normal physiology therefore localising the inhibitory activity of AT to endothelial surface of blood vessels.
The half life of AT is 3-5 days - production (by the liver) and turnover is highly regulated
AT deficiency (due to quantitative or qualitative defects in AT) leads to uncontrolled thrombin generation and fibrin deposition within the vasculature leading to increased thrombotic risk +/- insensitivity to heparin
What are the causes of antithrombin deficiency?
AT deficiency can be acquired or inherited
Acquired = diseases that cause reduced AT levels e.g.
- liver disease (primarily cirrhosis)
- nephrotic syndrome
- acute thrombosis (accelerated consumption)
- DIC (consumption)
- ECMO
- surgery/trauma
- asparaginase therapy (for ALL)
- heparins
- oestrogrens
Genetic = autosomal dominant with variable penetrance
- heterozygosity for a variant in SERPINC1 gene
- note do not see homozygosity for AT deficiency as not compatible with life
Resulting phenotypes characterised as type 1 and type 2 deficiency
- type 1 = reduced AT level
- type 2 = functional deficiency due to pathogenic variants
Is antithrombin affected by pregnancy?
No, not in normal pregnancies
However AT levels may decrease significantly with pregnancy-induced hypertension, PET or eclampsia
Also, patients with AT deficiency appear at particularly high risk of thrombosis during pregnancy
Is antithrombin considered an acute phase reactant?
No
Can antithrombin function be assessed by routine coagulation tests/ affects coagulation testing?
No - does not affect PT, aPTT or TT
When should you test for antithrombin deficiency?
Rarely
May test in cases of:
- suspected inherited thrombophilia based on family history or atypical presentation
- children with thromboembolism in absence of CVC
- suspected heparin resistance
- asparaginase therapy or ECMO
Can you test for antithrombin deficiency at the time of thromboembolic event?
No because thrombosis may cause a transient reduction in AT levels that could be misinterpreted as an underlying inherited deficiency
What is the best first test for Antithrombin deficiency?
Antithrombin-heparin cofactor assay
It is a functional assay that measures the ability of heparin to inhibit coagulation factor 2a (thrombin) or 10a (more specific) which requires AT activity
Why is the functional assay measuring the ability of heparin to inhibit Factor 10a preferred over inhibition of Factor 2a (thrombin) when testing for antithrombin deficiency?
Because factor 10a is inhibited by AT (heparin cofactor 1) alone via a heparin-dependent mechanism whereas thrombin can also be inhibited by a heparin cofactor 2 (thus differences in heparin cofactor 2 activity may affect assay results)
What is the lower limit of normal for Antithrombin activity?
80%
Most patients with hereditary AT deficiency have levels in the 40-60% range
When after a thromboembolic event should you test for antithrombin deficiency if you are going to test for it?
Most times should delay until patient recovers or is no longer receiving an anticoagulant
Exceptions:
- family members of individuals with AT deficiency for whom rapid diagnosis is important for care eg in setting of emergency surgery
- individuals receiving heparin therapy for whom a therapeutic aPTT cannot be achieved and/or additional thrombosis develops and for whom AT replacement therapy or change in anticoagulant might be indicated
- individuals receiving asparginase for whom AT replacement would be indicated if AT deficiency diagnosed
Note, if patient on direct Xa inhibitor (eg rivaroxaban) can test thrombin-based assay; if patient on direct thrombin-inhibitor (eg dabigatran) can test factor Xa-based assay
Warfarin does not affect antithrombin levels
Is genetic testing necessary for diagnosing antithrombin deficiency?
No, not routinely ordered
Demonstration of SERPINC1 mutation is confirmatory but not required
However do have to exclude acquired causes
How does the presence of antithrombin deficiency alter management for VTE?
- Often requires indefinite anticoagulation
- Preference for initial parenteral anticoagulation especially for severe thromboses
- Slight preference for warfarin over DOAC given more data and clinical experience plus able to monitor anticoagulant effect (using INR) and establish if people taking anticoagulant/was in target INR range if have recurrent event
(note this is important as some patients with AT deficiency are extremely thrombosis-prone and sustain recurrent VTE events despite therapeutic anticoagulation)
When might you use antithrombin replacement?
In some cases of AT deficiency with unusually severe thrombosis, recurrent thrombosis despite adequate anticoagulation or heparin resistance (especially those on ECMO, undergoing cardiopulmonary bypass surgery or on dialysis)
What other long-term management considerations are there for patients with antithrombin deficiency?
- Avoid estrogen containing contraceptives
- Thromboprophylaxis during pregnancy (usually with LMWH)
- Monitor AT levels during asparaginase therapy and provide LMWH thromboprophylaxis
What is the most common site of asparaginase-associated thrombosis?
Intracranial eg dural sinus thrombosis
(Therefore consider if headache, focal neurologic findings or encephalopathy when on asparaginase-chemotherapy)
What is the cause of Factor V Leiden (FVL)?
A point mutation F5 gene which encodes the factor V protein in the coagulation cascade
Factor V is a procoagulant that circulates in its inactive form in plasma - at the site of tissue injury, a small amount of thrombin activates factor V which then serves as a cofactor in the prothrombinase complex which cleaves prothrombin to generate more thrombin - that is, it amplifies the production of thrombin (which converts fibrinogen to fibrin leading to clot formation)
Meanwhile, thrombin also slows its production by creating a separate negative feedback loop by converting protein C to activated protein C which degrades factor Va and VIIIa reducing thrombin production (note aPC uses free protein S as a cofactor in these reactions)
The single point mutation in F5 (replacement of arginine with glutamine at amono acid 506) renders both active and inactive forms of Factor V insensitive to the actions of activated protein C (aPC) by abolishing the Arg506 cleavage site for aPC
This means FVL increases clotting by 2 changes:
1) activated FVL (procoagulant) cannot be cleaved by aPC
2) unactivated FVL (anticoagulant) cannot act as effective cofactor for aPC resulting in reduced degradation of FVa and FVIIIa
Therefore, FVL increases the risk of VTE
What is the mode of inheritance of FVL?
Autosomal dominant
99% are heterozygous for the variant
1% homozygous or pseudo-homozygous - disproportionate risk of VTE
What percentage of FVL heterozygotes will experience VTE during their lifetime?
5-10%
What is the FVL paradox?
The occurrence of isolated PE (ie without evidence of DVT) in individuals with FVL is less common than individuals without FVL
When should you suspect FVL?
- in someone with positive family history
- individual with VTE at young age <50
- individual with VTE in unusual location eg portal vein, cerebral vein
- individual with recurrent VTE
What test should you order to diagnose FVL?
Genetic test
- if positive family history
- if antiphospholipid syndrome
- if receiving anticoagulant that might interfere with results
- if positive functional assay
(Genetic testing can be done on peripheral blood, fairly straightforward and inexpensive and is unaffected by anticoagulants BUT it will not detect other hereditary causes of aPC resistance or acquired causes of aPC resistance)
Functional aPC resistance assays (2nd generation)
- first line for individuals not fitting above
(cheaper than genetic testing HOWEVER may be falsely abnormal if lupus anticoagulant present or falsely normal if taking DTI (dabigtran) or Xa inhibitor (apixaban etc)
What non-VTE conditions are associated with FVL?
Osteonecrosis
Legg-Calve-Perthes disease
How does the presence of FVL influence the management of VTE?
It doesn’t influence initial treatment of VTE
Doesn’t influence the decision of VKA or DOAC
May influence duration of anticoagulation although this is individualised; similar to general population, would be more likely to advise indefinite anticoagulation if VTE unprovoked, life-threatening, at unusual site or multiple episodes
Do FVL carriers (heterozygotes without personal or family hx of VTE) require any special treatment?
- VTEpr as per general population
- Avoid estrogen-containing contraceptives
- more likely to anticoagulate during pregnancy/post-partum if other risk factors present
- suggest leg exercises/ambulation when flying + consider compression stockings + consider low-dose aspirin (but not supported by high quality evidence)
- counsel on risk of VTE/signs etc
Is it worth covering individuals with FVL with low dose LMWH during pregnancy to prevent miscarriage or miscarriage?
No - 2023 ALIFE2 trial suggested nil benefit
What are other acquired causes of activated Protein C resistance?
Cancer
Proteinuria
Obesity
Smoking
Antiphospholipid antibodies
Pregnancy
Oestrogen / Menopausal hormone therapy
Increased factor VIII
Note also rare variants in Factor V other than FVL that produce the aPC resistance phenotype eg Factor V Cambridge etc
