Anticoagulation in Patients with Brain Metastases

Treatment:

  • Anticoagulate in patients with brain tumors and VTE except if risk of ICH is high: i.e.
    • melanoma mets
    • renal cell carcinoma mets
    • choriocarcinoma mets
    • thyroid carcinoma mets
  • treat x 3-6 months; long term if malignant gliomas
  • LMWH recommended versus warfarin
  • If risk of ICH high:
    • IVC filter if significant residual brain mets
    • if mets already removed / treated effectively and medical condition too unstable – anticoagulate

DVT Prophylaxis:

  • do not anticoagulate except in post-operative period
  • use SCDs with post-op LMWH or UFH 12-24 hours after surgery
  • cotninue prophylaxis until ambulation resumed

 

REFERENCE:

Uptodate. “Anticoagulant and antiplatelet therapy in patients with brain tumors.” Accessed 08/12/2016.

Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25:5490.

 

Platelet Response / ARU / PRU

VerifyNow for Clopidogrel:

  • Values less than 194 PRU are specific evidence of a P2Y12 inhibitor effect

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VerifyNow for Aspirin:

  • ≤ 549: Evidence of platelet dysfunction due to aspirin
  • > 550: No evidence of aspirin-induced platelet dysfunction

 

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ASA-specific VerifyNow uses arachidonic acid as an agonist for platelet aggregation onto fibrinogen-coated beads.

VerifyNow (P2Y12) uses adenosine diphosphate and is more commonly utilized to detect platelet dysfunction due to clopidogrel.

Degree of platelet aggregation is recorded as aspirin reaction units (ARUs) or P2Y12 reaction units (PRUs).

Abnormally functiong platelets are defined as ARU <550 or PRU 208 (U of Cincinnati lab normal value, cutoff not universally defined).

 

VerifyNow Reference Guide

Clinical Value of the VerifyNow System

 

REFERENCES:

Click to access mvn0005_-_verifynow_pocket_guide_1.pdf

Click to access CLMA_Educ_Day_Presentation_-VerifyNow_2-18-14.pdf

Martin, G., Shah, D., Elson, N., Boudreau, R., Hanseman, D., Pritts, T., Makley, A., Foreman, B. and Goodman, M. (2018). Relationship of Coagulopathy and Platelet Dysfunction to Transfusion Needs After Traumatic Brain Injury. Neurocritical Care.

 

Hypercoagulable Panel

Checklist for hypercoagulable work-up

  • *Antithrombin III Activity
  • *Prothrombin Gene Mutation
  • *Factor V (5) Leiden Gene Mutation
  • Factor VIII (8) Activity
  • aPTT-LA (Lupus Sensitive Reagent)
  • Anticardiolipin Antibody (IgG, IgM, IgA)
  • Beta 2 glycoprotein
  • Russell Viper Venom Time (dilute)
  • *Homocysteine
  • *Protein C Activity
  • *Protein S Activity
  • ESR CRP ANA
  • MTHFR
  • SPEP
  • Lipoprotein A
  • Plasminogen activator inhibitor

*Shani list, also add Lupus anticoagulant, Vit B12 levels

Rarer causes:

  • Alpha-macroglobulin deficiency
  • Dysfibrinogenemia
  • Factor V deficiency, excess
  • Factor VII excess
  • Factor VIII excess
  • Factor XI excess
  • Heparin cofactor II deficiency
  • Hyperfibrinogenemia
  • PAI-1 excess
  • Plasminogen deficiency
  • tPA deficiency
  • TFPI deficiency
  • Thrombomodulin deficiency

 

References

“Hypercoagulability Panel – Machaon Diagnostics”. Machaon Diagnostics. N.p., 2016. Web. 30 Mar. 2016.

“Hypercoagulable States”. Clevelandclinicmeded.com. N.p., 2016. Web. 30 Mar. 2016.

Treatment of Vasogenic Edema

Pathogenesis:  production of VEGF, glutamate, leukotrienes (increases permeability of tumor vessels) and absence of tight endothelial cell junctions in tumor blood vessels (respond to VEGF and basic fibroblast growth factor)
 Presentation1
Gliomas, meningiomas, metastatic tumors –> secretes VEGF –> binds to VEGFR1 and VEGFR2 (surface of endothelial cells –> formation of gaps in endothelium –> fluid leakage into brain parenchyma –> vasogenic edema –> spreads more in white matter (lower resistance than gray matter) –>  disrupts synaptic transmission, alters neuronal excitability –> HA, seizures, focal deficits, encephalopathy, herniation
DEXAMETHASONE
Advantages:  Lack of mineralocorticoid activity, less fluid retention; lower risk of infection and cognitive impairment
Mechanism:  Upregulates Ang-1 (BBB-stabilizing factor) and downregulates VEGF in astrocytes and pericytes; increases clearance of peritumoral edema by facilitating transport of fluid into ventricular system
Dosage:
  • Severe symptoms: 10mg IV loading dose then 4mg QID or 8 mg BID
  • Lower doses (1-2mg QID) may be as effective and less toxic
  • Long half life allows BID dosing
  • Improves within hours, maximum benefit within 24-72 hours, neuroimaging may not confirm until at least 1 week
  • If 16mg/day insufficient, may increase up to 100mg/day
  • Taper:  once improved, taper by 50% every 4 days
Guidelines:
  • severe symptoms:  16mg/d or more
  • milder symptoms: start 4-8mg daily
  • asymptomatic: steroids not recommended
  • taper over 2 week period or longer
Complications:
  • Insomnia, essential tremor, hiccups
  • GI complications
  • Steroid myopathy – prox weakness in week 9-12
  • PCP infection – risk increases while tapering steroids; fever and dyspnea and dry cough but can be subtle and nonspecific
Novel treatments:
  1. bevacizumab (anti-VEGF monoclonal antibodies)
  2. corticotrophin-releasing factor
  3. COX-2 inhibitors?

 

 

 

DDAVP

DESMOPRESSIN:

  • vasopressin analogue
    • does not have vasoconstriction / antidiuretic effects of vasopressin
  • DDAVP = deamino-arginine vasopressin

 

Mechanism of Action:

  • Increases cAMP in renal tubular cells –> increases water permeability –> decreased urine volume
  • Increases plasma vWF, F8 and t-PA –> shortened aPTT and bleeding time

 

DOSAGE:

1. Uremic bleeding (off-label): 0.4 mcg/kg IV over 10 minutes

  • corrects bleeding time in 75% of patients with renal failure
  • renal failure with significant bleeding: 1 dose given empirically; 2nd dose 8-12h later
  • recommended dose: 0.3 ug/kg IV, SQ or 30 ug/Kg intranasally
  • effect lasts 6-8h, repeated dosing leads to tachyphylaxis; responsiveness restored if drug withheld x 3-4d

2. Prevention of surgical bleeding in uremia (off-label): 0.3 mcg/kg IV over 30 minutes

3. Diabetes insipidus:

  • IV, SubQ: 2 to 4 mcg daily (0.5-1 mL) in 2 DD or 1/10 of maintenance intranasal dose
  • Oral: 0.05 mg BID, titrate total daily dose to adequate antidiuresis (0.1 to 1.2 mg in 2-3 DD)
  • Intranasal (100 mcg/mL nasal solution): 10-40 mcg OD (0.1 to 0.4 mL) or in 2-3 DD

4. Hemophilia A and von Willebrand disease (type 1):

  • IV: 0.3 mcg/kg by slow infusion; may repeat dose if needed; if used preoperatively, administer 30 minutes before procedure
  • Intranasal (using high concentration spray [1.5 mg/mL] [eg, Stimate]): <50 kg: 150 mcg (1 spray in a single nostril); ≥50 kg: 300 mcg (1 spray each nostril); repeat use is determined by the patient’s clinical condition and laboratory work. If using preoperatively, administer 2 hours before surgery.

 

5. Reversal of Aspirin in ICH:  0.4 ug/Kg x 1 dose (max dose 20 ug) 

Capture

 

 

 

 

DDAVP (From NCS Guidelines)

  1. Mechanism of Action (reversal of aspirin)
    1. vasopressin analog, little vasopressor activity
    2. increases endothelial release of large factor VII: vWF multimers
    3. may increase platelet membrane glycoprotein expression, promoting platelet adhesion to endothelium
  2. Data
    1. shown to reduce bleeding time, normalize hemostasis in uremic patients undergoing surgery; improved platelet function in uremic patients exposed to aspirin
    2. improved platelet function demonstrated in healthy populations on ASA / COX-1 inhibitors or ADPr inhibitors.
    3. shown to significantly reduce blood loss and improve thrombus formation in cardiac surgery patients exposed to ASA pre-op
  3. Reported side-effects:
    1. facial flushing, peripheral edema, hypervolemia, increased UO, hyponatremia;
    2. rare reports of cerebrovascular thrombosis

“Because of the low risk of serious side effects, the relatively low cost, and the suggestion of benefit in the aforementioned studies, we suggest consideration of a single dose of DDAVP (0.4 mcg/kg) in intracranial hemorrhage patients exposed to antiplatelet agents. In patients deemed appropriate (e.g., those undergoing a neurosurgical procedure), DDAVP can be used in addition to platelet transfusion.” NSC Guidelines

 

References

Marino, Paul L, and Kenneth M Sutin. The ICU Book. Philadelphia: Lippincott Williams & Wilkins, 2007. Print.

Uptodate.

Frontera, J., Lewin, J., Rabinstein, A., Aisiku, I., Alexandrov, A., & Cook, A. et al. (2016). Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage. Critical Care Medicine44(12), 2251-2257. doi: 10.1097/ccm.0000000000002057

KCentra Contents and Dosing

kcentra dose and contents

 

#1

Kcentra: coumadin reversal in acute major bleeding or need for urgent surgery:  

  • Pretreatment INR: 2 to <4: Administer 25 units/kg; maximum dose: 2,500 units
  • Pretreatment INR: 4 to 6: Administer 35 units/kg; maximum dose: 3,500 units
  • Pretreatment INR: >6: Administer 50 units/kg; maximum dose: 5,000 units

*Dosage expressed in units of factor IX activity
*give concurrent vitamin K
*Repeat dosing is not recommended (has not been studied).

 

#2

Life-threatening hemorrhage with DOACs: (off label)

Optimal dosing not established

European Heart Rhythm Association, 50 units/kg (+25 units/kg if clinically necessary) recommended based on limited evidence in healthy volunteers

ICH due to various antithrombotic agents (NCS/SCCM [Frontera 2016]):

  • apixaban, edoxaban, rivaroxaban:
    • 50 units/kg if ICH within 3 to 5 terminal half-lives of drug exposure or when liver failure co-exists.
  • argatroban, dabigatran [if idarucizumab unavailable], bivalirudin, desirudin:
    • 50 units/kg if administered within 3 to 5 half-lives prior and no renal failure or there is renal impairment leading to drug exposure beyond 3 to 5 half-lives

 

FIXED vs. VARIABLE DOSE

Advantages of fixed dose KCentra:

  1. eliminates need for dose calculation based on patient-specific variables
  2. earlier start of hemostasis – limits hematoma enlargement?
  3. easier administration, no complex tables, reduction of door-to-needle time
  4. ?better clinical outcome

Retrospective study from Netherlands – fixed dose 1000 IU fIX PCC, ffd by 500 IU if INR>1.5, used Cofact (Sanquin BV) which contains FII FVII FIX FX and PrC and PrS, no activated factors or heparin. CONCLUSION:  that fixed dose required further dose/s to achieve target INR.  Door-to-needle time shorter, but not significant.  ?clinical outcome unknown.

Bottom line:  For now, calculate dose based on weight and INR.

 

 

 

 

 

References

“Prothrombin complex concentrate, 4-factor, unactivated, from human plasma”. Uptodate.com. Accessed 13 Dec. 2016.

Kcentra product insert.

Abdoellakhan, Rahat Amadkhan et al. “Fixed Versus Variable Dosing Of Prothrombin Complex Concentrate In Vitamin K Antagonist-Related Intracranial Hemorrhage: A Retrospective Analysis”. Neurocritical Care 26.1 (2016): 64-69.

DIC

Disseminated Intravascular Coagulation Scoring System

dicscore ISTH Scoring System

 

TREATMENT:

  • no specific treatment other than that directed against predisposing condition
  • bleeding – replace platelets and coagulation factors
    • cryoprecipitate 10 units = fibrinogen 2.5 g  –> but this rarely helps, consumption of platelets and coagulation proteins can aggravate thrombosis
  • heparin is ineffective in retarding microvascular thrombosis (due to depletion of antithrombin III)
    • give heparin with AT-III? – 90-120 units load then 90-120 units daily x 4 days (no evidence for improvement in mortality)

 

References:

Marino, Paul L, and Kenneth M Sutin. The ICU Book. Philadelphia: Lippincott Williams & Wilkins, 2007. Print.

Kiwon Lee.  NeuroICU Book