Heme Flashcards
Pathogenesis of anemia of chronic disease
- Hypoproliferative anemia
- Release of cytokines from T cells and monocytes that stimulate the uptake an storage of iron in macrophages/monocytes
- Hepcidin is also stimulated, which contributes to more iron storage
- Suppresses EPO production by the kidneys
- Results in iron-deficient erythropoeisis despite marrow replete with iron
Presentation
- Normochromic
- Normocytic
- Usually mild/mod (Hb 80 - 95)
- Low retic count
Iron studies
- Low serum iron
- Low TIBC (elevated in Fe deficiency)
- Low % iron sat
- Normal or elevated ferritin
Chronic blood loss - lab workup
Chronic
- Low ferritin (low iron stores)
- Normal serum iron early, then falls with time
- Normal % iron sat early, then falls over time
- Hb typically preserved until severe iron deficiency occurs
- Target cells and pencil cells in severe deficiency
Treatment of anemia from chronic blood loss
- Source control
- Stop the bleeding if possible (surgical, endoscopically, radiation) - Iron supplementation
- If iron deficiency is present
- PO iron salts taken in 3-4 separate doses 1 hr prior to meals (cheaper)
- polysaccharide iron complex (expensive, no evidence they are better tolerated or provide better treatment than iron salts)
- Consider IV iron if patients are intolerant of PO iron, have intestinal malabsorption, or are losing iron more quickly than can be replaced with PO supps
3. Blood transfusion if severe anemia
IV iron formulations
- Calculate required dose
dose (mg) = hemoglobin deficit (g/dL) x body weight (lbs)
- In practice, no benefit over 1000mg of IV iron (give in divided doses)
- Typical to give 1000mg over multiple infusions as this will correct anemia without causing iron overload
Iron sucrose vs Iron dextran
- Iron dextran is associated with anaphylaxis in less than 1%, but not as commonly used for that reason
Megaloblastic anemia
- May be related to nutritional deficiencies in folate or B12
- Folic acid level often decreased compared to general elderly population in cancer patients, especially in major weight loss - anemia appears 4 months following inadequate intake
- Folic acid level may be an insensitive marker of deficiency
- Supplementation of folic acid 1mg PO daily
Anemia due to bone marrow infiltration
- Less common than anemia of chronic disease, iron deficiency, or nutritional deficiencies
- All malignancies can metastasize to marrow, but more common with lung, breast and prostate
Presentation:
- Leukoerythroblastic (immature nucleated RBCs, myeloid WBC precursors, teardrop red cells)
- If mild/mod infiltration, minimal changes to CBC
- If marrow significantly affected, may see severe anemia, high WBCs, and any variation of platelet numbers
Diagnosis
- Smear
- Can use a marrow bx to confirm, but may not be clinically necessary
Thrombocytopenia
- Commonly occurs in the context of pancytopenia due to MDS or heme malignancies
- Spontaneous bleeding unlikely until below platelet count of 20
- ICH unlikely until below platelet count of 10
Neuropenia
- most commonly due to bone marrow failure from myelosuppressive chemo, disease infiltration of bone marrow, or intrinsic bone marrow failure
- Definition: ANC < 1.5 (severe is < 0.5)
Febrile neutropenia: Definition, work up, management
Febrile neutropenia:
- Single or temp > 38.3 or sustained temp >38 for one hour
AND neuts <0.5 or <1 with predicted nadir of 0.5
- Nadir typically occurs 7-14 following administration of each cycle of treatment
- Source of infection often not identified (only in 20-30% of patients), and may be due to patient’s own flora
Investigations: Blood cultures, urine, sputum, any skin/mucosal lesion, stool, CXR, basic blood work including liver panel
Treatment:
- No routine use of G-CSF, but start broad spectrum abx immediately
Treatment of FN (specifics)
High risk patient:
- Hemodynamically unstable
- Altered mental status
- New pulm infiltrate
- Hepatic or renal dysfunction
- Underlying chronic lung disease
- Mucositis
- Inpatient at time of dx
- Prolonged neutropenia
- Expected neutropenia >7 days (generally in induction chemo for SCT or leukemia)
- Heme malignancy
- Comorbidities
- Higher intensity chemo
High risk patients Rx:
- Antipseudomonal beta lactam (Pip-tazo, mero, consider ceftaz).
- Consider Vanco in SSTI or hemodynamic instability
Low risk patient Rx:
- Most patients receiving chemo for solid tumours are low risk for complications requiring hospitalization, in the absence of other signs or symptoms
- Cipro 750 BID (alternative levoflox) + Amox/clav
Factors making a patient high risk with FN
High risk patient:
- Hemodynamically unstable
- Altered mental status
- New pulm infiltrate
- Hepatic or renal dysfunction
- Underlying chronic lung disease
- Mucositis
- Inpatient at time of dx
- Prolonged neutropenia
- Expected neutropenia >7 days (generally in induction chemo for SCT or leukemia)
- Heme malignancy
- Comorbidities
- Higher intensity chemo
DIC
- Tissue factor released from vascular endothelial damage, trauma, cytokines, etc, triggering coag cascade
- Microthrombi formed in circulation which perpetuate cascade
- Over time, clotting factors consumed and then excessive bleeding occurs
May be acute (bleeding predominates b/c of depletion of platelets, fibrinogen, clotting factors)
May be chronic and somewhat compensated (thrombosis predominates b/c liver can keep up with coag factors)
Major causes:
- Sepsis
- Trauma/surgery
- Malignancy (especially APML and adenocarcinoma)
- Obstetrical complications
Diagnosis of DIC
- Thrombocytopenia
- MAHA (non-immune hemolysis with low Hb, schistocytes on smear, high bili)
- High INR/PTT
- Low fibrinogen (note may be normal in the context of malignancy)
- Elevated D-dimer
Management of DIC
- Supportive care i palliative patients - note that mortality ranges from 31-86%
- Treat underlying cause (especially infection)
- Platelets if Plt <20 or bleeding
- Cryo for Fibrinogen < 0.5
- FFP if INR elevated and bleeding
- May consider heparin for chronic DIC with thrombosis predominant
RBC Transfusions in palliative care
Indications
- Fatigue and dyspnea, but no RCTs to guide (observational data only)
- No guidelines, decision is individual
- In non-palliative patients, transfusion threshold is usually 70 in non-cardiac patients so long as there is no evidence of bleeding
Platelet transfusions in palliative care
- Prophylactic transfusion for patients with Plt < 10 given risk of ICH
- If actively bleeding, target Plt > 50
Transfusion reactions - frequency
Frequency of transfusion reactions:
- Urticaria (1 in 100)
- TACO (1 in 100)
- Fever (1 in 300)
- Delayed hemolytic reaction (1 in 7000)
- TRALI (1 in 10 000)
- Acute hemolytic reaction (1 in 40 000)
- Anaphylaxis (1 in 40 000)
- Bacterial sepsis (1 in 250 000)
- HBC (1 in 7.5 million)
- HCV (1 in 13 million)
- HIV (1 in 21 million)
Presentation of Acute hemolytic reaction
Hemolytic transfusion reaction
- Occurs within 24 hours after transfusion - Suspect with hypotension, hemoglobinuria, renal failure, back pain, chills, fever, signs of DIC.
Management:
- IV NS to promote diuresis and maintain BP
- Manage DIC and hemorrhage
Presentation of TRALI
TRALI
- Typical onset within 6 hours of transfusion, presents with dyspnea, bilateral lung infiltrates, fever, tachycardia, tachypnea, hypotension
- Note BNP will be low
Treatment:
- Stop transfusion
- Diuretics and steroids NOT helpful
- Mechanical ventilation PRN
- Typical resolution within 24-72 hours
Delayed hemolytic transfusion reaction
Presentation:
- Occurs 5-15 days post transfusion
- Coomb’s positive
- Antibodies result in sequestration and phagocytosis of RBCs in the liver and spleen. Often clinical silent, but may present with low grade fever or jaundice
- Indirect hyperbilirubinemia (jaundice)
- Hemoglobinuria
Criteria for minor blood transfusion reaction
- Hives or rash < 25% of body and no other symptoms
- Fever is associated with no other symptoms
Febrile non-hemolytic transfusion reaction
- Fever during transfusion or up to 4 hours after
- Chills, rigors, N/V, hypotension without fever
- Symptoms are self limited, respond to tylenol
If fever is the only symptom:
- Consider tylenol
- Consider restarting transfusion
If any symptom other than fever:
- Ensure investigations completed to rule out acute hemolysis (CBC, lytes, bili, INR/PTT, fibrinogen, LDH)
Use of erythropoeitin in palliative patients
- Most common use is in anemia associated with advanced renal disease
- May be used in some cancers, but there is concern that it can worsen tumour control
- Increased risk of hypertension and VTEs
VTE in palliative care (incidence, pathogenesis)
- 15% of patients with cancer will develop symptomatic VTE
- 10% of patients with idiopathic VTE will be diagnosed with cancer within a year
- Due to venous stasis, endothelial injury, and hypercoagulability
Treatment of cancer-associated VTE
LMWH
- Only dalteparin is approved in canada at 200U/kg in first month, then 150 U/kg thereafter
DOACs
- Similar rates of recurrent VTE compared to LMWH (4-8%)
- Similar rates of major bleeding compared to LMWH (more with edoxaban)
- More GI bleeding in patients with GI cancers, especially with edoxaban
Use a DOAC if not a GI malignancy!
- Apixaban 10mg BID x 1 week, 5mg BID thereafter (no bridge)
- Rivaroxaban 15mg BID x 3 weeks, then 20 mg daily
Duration:
- at least 3-6 months, continue if patient remains on chemo, has metastatic disease, relapsed disease, or other ongoing risk factors
Monitoring:
- CBC, weight, renal function q3 months
Recurrence:
- For LMWH, increase dose by 25%
- If on a DOAC, switch to LMWH
Causes of bleeding in patients with advanced disease
- Cancer invasion or destruction
- Tumour or metastatic lesions often very vascular and friable
- Renal cell ca, melanoma, and choriocarcinoma are particularly vascular
- Risk of erosion into vessels, especialy with head and neck cancer - Treatment related causes
- Chemo and rads affect hemostatic mechanisms and can result in mucositis or damage to structures
- GVHD is also associated with risk of hemorrhagic complications - Thrombocytopenia/marrow failure
- Secondary to myelosuppressive therapy
- Marrow invasion - Nutritional deficits
- Especially Vit K - Drugs
- NSAIDs, anticoags, SSRIs - Coagulation disturbances
- DIC associated with leukemias, mucin-producing carcinomas of prostate, pancreas, lung, breast, ovary, and GI tract
Sentinel bleeds
- Small, prodromal bleeding episodes days or hours before the rupture of a larger artery (especially in malignant neck wounds or hemoptysis)
Major hemorrhage
Arterial
- Defined as loss of >1.5 L in 30 secs
Hemoptysis
> 100mL in 24 hrs
Associatd with high mortality
Presentation of carotid blow out
- Associated with soft tissue necrosis in the neck and mucocutaneous fistuals
- Threatened carotid blow out
- Artery is clinical exposed or there is radiological evidence of carotid invasion - Impending carotid blow out
- Sentinal bleed has occurred and settled spontaneously or with treatment - Acute carotid blow out
- Rupture with profuse bleeding
Risk factors for bleeding in cancer patients
- Plt < 20
- Large head and neck cancers
- Large centrally located lung cancers
- Refractory acute and chronic leukemias
- MDS
- Severe liver disease/metastatic liver disease
- HCC
- Oral anticoagulants
- High dose rads
Risk factors for terminal hemorrhage in head and neck cancers
- Radical neck dissection
- High dose rads
- Post op healing problems
- Visible arterial pulsation
- Pharyngocutaneous fistula
- Fungating tumours with artery invasion
- Direct observation during surgery or imaging of artery wall invasion
- Sentinal bleed
Communication regarding risk of terminal bleed
- Established goals of care important
- Arguments for and against full disclosure, but in general there needs to be a balance between information needs and potential psychological impact as the event can be very distressed
Investigations in bleeding
- Warranted especially if patient is not at EOL
- Consider CBC, INR, PTT, and fibrinogen
- Consider scopes or angiography to identify and treat sources of bleeding
- MRI may be useful in cases where there is concern re: carotid blowout
Prevention of variceal bleeding
Management of varices:
Child A cirrhosis, small varices without red signs (red spots): - Expectant management only with upper endoscopy q6 months to monitor.
Small varices with red signs and/or Child B or C cirrhosis:
- Non-selective beta blocker (reduces likelihood of progression and reduces bleed risk).
- Consider ligation if patient is unable to tolerate a BB or if there is progression with a BB.
Medium varices:
- Nonselective BB or ligation
Large Varices:
- Ligation, with BB as alternative if patient unwilling to undergo ligation
Prevention of bleeding in patients with prostate cancer
- Rectal bleclometasone topically in patients receiving rads may reduce bleeding risks
Prevention of bleeding from ulcerated wounds
- Avoid dry dressings
- Use non-adherent dressings
- Maintain a moist wound bed
- Gently irrigate rather than swab
Dressings for bleeding
Pressure
- For minimal bleeding, compressive dressings typically adequate
- Inflatable balloons with catheters can be used to control severe posterior nasal bleeding (caution, as it may cause tissue necrosis)
Packing
- With saline-soaked dressings/swabs or hemostatic dressings useful for bleeding from accessible hollow organs (e.g. nose, rectum, vagina)
- Addition of hemostatic agents may be used (silver nitrate, epi, cocaine)
- Reduce frequency of dressing changes and avoid adherent dressings
Topical hemostatic agents: Absorbable products
Absorbable products
- Least expensive
Gelatin foams
- Mixed and applied as paste, can be combined with thrombin to provide a physical matrix for fibrin deposition
- Fully absorbed in 4-6 weeks
Oxidized Cellulose
- sold as sponges/pads
- applied dry and expand and dissolve in 2-6 weeks
Microfibrillar collagen
- sponge and powder forms
- platelets adhere to the fibres and are activated
- Effective in heparinized patients but not in thrombocytopenia
- useful in large areas of parenchymal bleeding
Topical hemostatic agents: Biologic agents
Premise - thrombin forms basis of a fibrin clot by promoting conversion of fibrinogen to fibrin (requires fibrinogen).
- Biologic agents include topical thrombin, fibrin sealants, and platelet sealants
Topical thrombin
- may be applied directly to a bleeding site or soaked in a gelatin sponge
- Requires frozen storage and thawing first
Fibrin sealants
- Thrombin and fibrinogen delivered through a dual-syringe delivery system mixing the two components as applied to form a stable fibrin clot
- Coagulation occurs independently from patient blood
- Useful in patients with severe coagulopathy and may be instilled via bronchoscopy
- May cause immunological reactions
Platelet sealant
- Thrombin/collagen suspension that reacts with patient’s own plasma to form a fibrin/collagen clot
- Resorbed in 30 days
- Requires centrifugation of patient’s own plasma and significant processing - typically not practical
Topical hemostatic agents: Alginates
- Fibre dressings containing alginic acids (mannuronic and guluronic) which are extracted from seaweed)
- Available as pads or ribbons
- Forms a gel on contact with wound exudate and prevents the wound from drying out, assisting in autolytic debridement
- Requires secondary cover dressing to keep them in place
- Rinse away with saline irrigation so as not to disrupt granulation tissue
Use:
- Wounds with large amount of exudate (not useful on large volume basis)
- Deep, undermined wounds as the risk of infection/inflammation is reduced with the alginate dressing left in situ
Change q12-48 hrs, but can be left up to 7 days
Topical hemoatstatic agents: Astringents, sclerosing, vasoconstrictor agents
- Induce chemical cauterization and control minor to moderate bleeding
Silver nitrate
- Strong oxidizer causing tissue coagulation
- Useful for epistaxis on a wooden applicator
- Useful instilled at low concentrations for bladder bleeding (may cause stenosis)
Aluminum-based solutions
- Alum bladder irrigation for hematuria
- Sucralfate enemas for radiation proctitis or mixed with KY jelly for application directly to bleeding wounds
Topical formalin
- Useful for radiation proctitis, vaginal tumours, cutaneous ulcers
- May be done as part of intravesicular bladder irrigation
- (Associated with severe adverse effects - spasms, renal failure, retroperitoneal fibrosis, incontinence, reduced bladder capacity, death)
Treatments for hematuria
- CBI in hopes of clot formation (generally first line)
FIRST:
- Watch to ensure the bladder outlet does not become obstruction which can lead to urosepsis, bladder rupture, and renal failure
- If a clot occurs, use a hematuria catheter (large diameter, stiff) to evacuate and ensure all clots removed prior to CBI. May require cysto if clots cannot be evacuated.
Other:
- Alum bladder irrigation (avoid in renal impairment or with very large bladder tumours)
- Silver nitrate 0.5-1% instilled for 10-20 minutes (risk of ureteral stenosis)
- Radiation (if from a malignant source)
- Percutaneous transcatheter arterial embolization (if severe)
- PO TXA (caution re: clot formation as may lead to obstruction)
Treatments for bleeding skin wounds
- Absorbable products (gelatin foams, +/- thrombin)
- Microfibrillar collagen (less effective with low platelets)
- Alginates (for oozing from malignant wounds) with a secondary cover dressing
- Sucralfate mixed with KY jelly
- TXA applied topically, 500mg tablets crushed and dissolved in 5mL of normal saline, soaked in gauze and applied for 10 mins
- PO TXA (1g daily)
Treatments for bleeding proctitis/rectal bleeding
- Topical formalin
- Sucralfate enemas BID
- PO TXA
Treatments for vaginal bleeding
- Packs soaked with formaldehyde or acetone
- Acetone soaked packs (especially in patients who have previously undergone radiotherapy)
- Topical formalin (can be used for cervical tumours) - (Associated with severe adverse effects - spasms, renal failure, retroperitoneal fibrosis, incontinence, reduced bladder capacity, death)
- Radiation for cervical CA or uterine CA bleeding
- PO TXA
- Percutaneous transcatheter arterial embolization (if severe)
Treatments for epistaxis
- Balloon catheter (caution for tissue necrosis)
- Silver nitrate on a stick
- Nasal packing
- Cocaine applied to cotton and packed into the nasopharynx
- Oxymetazoline spray (local vasoconstrictor)
Treatments for hemoptysis
- Radiation, especially in NSCLC (response rate typically 75%)
- Bronchscopy with instillation of hemostatic agents (epi, cold saline, thrombin/fibrinogen, fibrin sealant)
- Percutaneous transcatheter arterial embolization - Bronchial artery embolization
- Surgical resection in very select cases
- PO TXA
Treatments for GI bleeding
- Endoscopy if appropriate for ligation or injection
- Radiation for bleeding in gastric CA if ECOG 3 or better, expected survival > few months, failure/contraindication of other treatment modalities and oozing cancer bleeding with intractable pain
- Percutaneous transcatheter arterial embolization (adrenal artery for gastroduodenal bleeding)
- Surgery in select cases
- PO TXA
- Octreotide 50mcg subcut BID (infusion for variceal bleeds)
Treatments for bleeding head and neck wounds
- Percutaneous transcatheter arterial embolization (fewer complications than with endovascular management)
- Endovascular treatment (self expanding stents, insertions of balloons or coils)
- PO TXA (for slow oozes)
Endoscopic treatments for bleeding
- Cauterization or coagulation with electrocautery or cryotherapy
- Balloon tamponade
- Ligation (banding or endoclips)
- Injection of vasoconstrictor or sclerosing agents (epi, ethanol)
- Application of hemostatic agents
Systemic management of bleeding
TXA (aminicaproic acid is alternative type to also know, but less potent!)
- Antifibrinolytic agent that stabilize clots by blocking binding sites of plasminogen and decrease lysis of fibrin clots
- Useful for hemoptysis, hematuria (caution as clot formation risks obstruction), rectal bleeding, and in cases of fungating tumours
- Time to response 2-4 days
- 1g PO qDaily, then continue for7 days after bleeding has stopped. May dose increase to a max of 2g QID
- IV formulation also available.
Side effects:
- N/V/D (25%)
- Generally dose dependent
- VTE uncommon
- Dose reduce in renal impairment
Management of known variceal bleeds
- Avoid BB in acute bleeds
- Avoid over resuscitation
- Blakemore tube can be used as a temporizing strategy
- Start octreotide 50mcg/hr x 48 hrs (reduces splanchnic flow and pressure via vasodilation)
- Give panto IV bolus, then infusion of 8mg/hr
- Give IV CTX
- Call GI for a scope
- No role for TXA
Vitamin K
- Useful for bleeding from liver disease, warfarin, and DIC
- PO preferred (less likely to cause anaphylaxis) but slower onset of about 12 hrs
- Can be given IV for 4 hr onset
Management of INR in warfarin
If INR < 5, hold warfarin or lower dose
Levels 5 - 10 - hold warfarin, give 1mg vit K PO
INR > 10, risk of ICH, give 2.5 - 5mg PO vit K
If bleeding or needs rapid full reversal, consider vit K or octaplex
Thrombocytopenia - management
- Transfuse for Plt < 10 (risk ICH) (can also consider prophylactic TXA)
- Plt > 50 generally acceptable for most procedures/surgeries
- Plt >100 for neurosurgery or optho procedures
- Avoid transfusion in TTP (may precipitate thromboses)
- Consider immune-mediated refractoriness if there is minimal response to transfusion (look for anti-HLA antibodies)
Palliative setting
- short life span of transfused placelets (3-4 days) means they are of limited utility
- Platelet transfusions are not without risks (acute febrile episodes, alloimmunization, infection)
Consider for:
- Continuous bleeding of mouth and gums
- Overt hemorrhage
- Extensive and painful hematomas
- Recent disturbed vision in the setting of thrombocytpenia
- Severe and recent HA in the setting of severe thrombocytoepnia
- Severe anemia and thrombocytopenia
Use of FFP
- Contains all plasma clotting factors and is used to correct severe clotting factor deficiencies in urgent situations
- E.g. DIC, liver disease
Reversal of DOACs for major bleeding
- TXA not beneficial
- Prothrombin complex concentrate (Octaplex) may be beneficial (especially with Rivaroxaban and Apixapan)
- FFP likely ineffective, as is cryo
Dabigatran - give idarucizumab, or PCC as an alternate
Use of Cyro
- Concentrated blood component that contains fibrinogen, factor VIII, and vWF
- Used for patients with reduced fibrinogen activity
Indications:
- Bleeding or prior to an invasive procedure
AND
- hypofibrinigenemia due to liver disease, consumption (DIC), dilution (massive transfusion)
Note that recombinant factors can be used for hemophilia von Willebrand disease, leaving cryo useful only if these are not otherwise available
Management of terminal hemorrhage
Three categories:
- General supportive measures (dark towels, staying with the patient and providing reassurance, sedatives)
- Resuscitation if appropriate (fluids)
- Specific measures to stop the bleeding (surgery, wound packing, hemostatic agents, interventional radiology)
Workup for gross hematuria
- Screen for coagulopathy
- Cystourethroscopy
- Upper urinary tract imaging (CT urogram or retrograde pyelography)
- Depending on results, may go to uretoscopy and endoscopic fulguration
