Deep Vein Thrombosis- PN

Definition DVT è thrombus in deep vein.

Prevalence Estimated 1 per 1,000 people and contributes to 60,000–100,000 deaths annually.
The 30-day mortality rate > 3% in patients with DVT who are not anticoagulated, and this mortality risk increases 10- fold in patients who develop
PE
Pathogenesis Virchow’s Triad ( first described in 1856) implicates three contributing factors in the formation of thrombosisè
1) changes in the lining of the vessel wall (wall damage).
2) changes in the flow of blood (stasis or low flow).
3) changes in the constituents of the blood (hypercoagulability).
Venous stasis è the most consequential of the three factors, but stasis alone appears to be insufficient to cause thrombus formation. However,
the concurrent presence of venous stasis and vascular injury or hypercoagulability greatly increases the risk for clot formation. Venous thrombosis
tends to occur in areas with decreased or mechanically altered blood flow such as the pockets adjacent to valves in the deep veins of the leg.
While valves help to promote blood flow through the venous circulation, the potential locations for venous stasis and hypoxia.
As blood flow slows è oxygen tension declines with a coincident increase in haematocrit.
The hypercoagulable micro-environment that ensues may downregulate certain antithrombotic proteins that are preferentially expressed on
venous valves including thrombomodulin and endothelial protein C receptor (EPCR). In addition to reducing important anticoagulant proteins,
hypoxia drives the expression of certain procoagulants. Among these is P-selectin, an adhesion molecule which attracts immunologic cells
containing tissue factor to the endothelium. Tissue factor serves as the primary nidus for thrombus formation. Thrombus formation appears to
require both tissue factor and P-selectin.

Natural history of DVT. The currents that occur as blood passes a valve encourage the deposition of thrombus within the valve cusp. The initial
platelet cluster on the vessel builds and grows toward the center of the vessel lumen. When a thrombus adheres to the endothelium, it stimulates
a hyperemic inflammatory response that begins the processes of organization. Thrombus retraction and organization destroys the valves in the
affected segment of the vein.

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 Risk Factors Risk factors of DVT can be distinguished as major (strong association with index DVT; likely responsible of index event), intermediate (moderate
association with index DVT, probably responsible of index event), or minor (weak association with index VTE; might partly explain index event).

Classification DVT classified into proximal and isolated distal DVT.

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 Diagnosis Clinical features:
- Asymmetrical swelling
- Warmth
- Pain

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 Wells score èscore for pre test probability assessment.

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 Diagnostic imaging

Ultrasound (US) è first- line imaging modality for diagnosis of proximal DVT.
Reason è safe, easily accessible, cost-effective, and reliable. It can accurately determine the size, chronicity, and degree of occlusion of a thrombus
and therefore better inform the decision to pursue medical management or interventional techniques.
The primary limitation of US is its diminished ability to detect distal DVT.
During the examination, an US probe is used to gently compress the vein of interest. Inability to compress the vein is considered diagnostic for
DVT. The clot can be further characterized with real-time imaging such as duplex and color- flow Doppler.

Contrast venography è gold standard for lower extremity DVT, but it is limited by a number of factors including availability, patient discomfort,
user-dependence, inadequate visualization, and patient-specific variables such as contrast allergy and renal insufficiency. Contrast media is
injected and serial radiographs are taken to visualize the deep venous system of the leg. A persistent filling defect in multiple views is considered
diagnostic for DVT.

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 CT venography è contrast media is injected into the arm and imaging is timed with opacification of the deep venous system in the lower
extremities. The exam is non-invasive, readily available, highly sensitive and specific for DVT, and provides the added benefit of cross-sectional
imaging. It may be particularly useful for identifying proximal DVT in patients with suspected PE.
Like conventional venography, it carries the same exposure to ionizing radiation and contrast media and is limited by renal insufficiency and
severe contrast allergy.

MR venography provides many of the same benefits as CT venography without the need for ionizing radiation. It has a similar sensitivity and
specificity for DVT. In addition, a variety of pulse sequences can be applied to visualize the deep venous system without the need for contrast
media. The disadvantages of MR venography are similar to other MR exams, namely patient intolerability, increased cost, and incompatible
hardware. Although not yet well studied, MR venography is becoming an increasingly viable option when US is not feasible in cases of suspected
DVT.

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 Tatalaksana

Deep vein thrombosis management consists of 3 phases:

1. Initial treatment (5- 21 days following diagnosis) è during this period, patients receive either parenteral therapy and are transited to VKA
or use high- dose direct oral anticoagulants (DOAC).
2. Long- term treatment (following 3- 6 months) è patients are treated with VKA or DOAC.
3. Extended treatment

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 Initial and long-term treatments are mandatory for all DVT patients. Decision of extended treatment (beyond first 3–6 months) is based on
benefit/risk balance of continued anticoagulation.

Anticoagulant in non cancer patient

NOACs è as first-line anticoagulant therapy in the absence of contraindication.
UFH is preferable è In patients with severe
renal failure (creatinine clearance<30 mL/min),
unstable renal function, or high bleeding risk.
(because short half- life and protamine sulfate
reversibility. Dosage 80 U/ KgBW/ IV bolus è
18 U/ kgBW/ hour/ sp. Monitoring: APTT.
Main disadvantage of UFH is its inter-individual
dose variability requiring laboratory monitoring
and dose adjustment. Additionally, UFH is associated with high risk of heparin-induced thrombocytopenia.
Low-molecular weight heparin (LMWH) is the parenteral treatment of choice. LMWHs are at least as effective as UFH and probably safer.
Fondaparinux can also be used as parenteral agent. Both LMWH and fondaparinux do not have specific antidote.
Dosage for enoxaparin è 1mg/ kgbw/ 12 hours/ sc or 1.5 mg/ kgbw/ 24 hours/ sc. For renal dose 1 mg/ kgbw/ 24 hours/ sc (CrCl < 30 ml/
minutes).
Dosage for fondaprinux è 5- 10 mg/ 24 hours/ sc (BW < 50 kg è 5 mg; BW 50- 100 kg è 7.5 mg; BW > 100 kg è 10 mg; no renal dose).

Anticoagulant in cancer patient

LMWH appears possibly superior to UFH in the initial phase (first 5– 10 days) of VTE treatment in patients with cancer.
For the long-term treatment, the CLOT trial èa cornerstone, showing for the first time that LMWH is more effective than VKA in reducing risk of
recurrent VTE in cancer patients
Duration of anticoagulant
For proximal DVT (with or without concomitant PE), 3- month anticoagulation is the best option if risk of recurrence is low (i.e. major transient/
reversible risk factors)
Provided bleeding risk is low, indefinite anticoagulation is the best . option for patients with high risk of recurrence (i.e. multiple VTE episodes in
absence of a major transient or reversible factor, VTE familial history, those with major thrombophilia).
Patients with DVT without identified risk factors and low bleeding risk are candidates for extended anticoagulation beyond the initial 3
months.

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 Consensus statement: initial and long-term management:
- Patients with proximal DVT should be anticoagulated for at least 3-months.
- Patients with isolated distal DVT at high-risk of recurrence should be anticoagulated, as for
proximal DVT; for those at low risk of recurrence shorter treatment (4–6 weeks), even at lower
anti- coagulant doses, or ultrasound surveillance may be considered.
- In the absence of contraindications, DOACs should be preferred as first-line anticoagulant
therapy in non-cancer patients with proximal DVT.
- Adjuvant CDT may be considered in selected patients with ilio- common femoral DVT,
symptoms <14 days, and life expectancy >1 year if performed in experienced centres.
- Primary acute DVT stenting or mechanical thrombus removal alone are not recommended
(lack of data).
Catheter- directed thrombolysis (CDT) è more efficient than systemic lysis (less bleeding) as
thrombolytic agent is directly administered within the clot.
- Vena cava filters may be considered if anticoagulation is contraindicated, their use in addition
to anticoagulation is not recommended.
One major complication è filter thrombosis. Therefore, anticoagulation should be started as
soon as contraindications resolve and retrievable filter rapidly removed.
- Compression therapy associated with early mobilization and walking exercise should be
considered to relieve acute venous symptoms.
Goals of compression è to relieve venous symptoms and eventually PTS.

Consensus statement: extended management

- Decision to discontinue or not anticoagulation should be individually tailored, balancing risk of recurrence against bleeding risk, taking
into account patients’ preferences and compliance.
- In the absence of contraindications, DOACs should be preferred as first line anticoagulant therapy in non-cancer patients. Currently low-
dose apixaban and rivaroxaban have shown their benefit in this setting.
- When VKAs are proposed, they should be administered at conventional intensity regimen (INR 2–3).
- Aspirin may be considered for extended treatment if anticoagulation is contraindicated.
- Endovascular recanalization may be considered in patients with chronic venous occlusion class CEAP 4–6.
- Regular (at least yearly) assessment of compliance and benefit/risk balance should be performed in patients on extended treatment.

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 - At anticoagulation discontinuation, venous US should be performed to establish a baseline comparative exam in case of recurrence.
Contraindications of anticoagulation therapy:
- Active bleeding
- Hemophilia or other hemorrhagic tendencies
- Severe liver disease with elevated baseline prothrombin time
- Severe thrombocytopenia (platelet count < 20000/ mm2)
- Malignant hypertension
- Inability to meticulously supervise and monitor treatment

Special situations Upper extremities DVT

- Upper extremities DVT (UEDVT) accounts for 10% of all DVTs
with an annual incidence of 0.4–1.0/10.000 persons.
- Incidence rises because of increasing use of central venous
catheters, cardiac pacemakers, and defibrillators.
- About 20–30% of UEDVT are primary comprising those
caused by anatomic abnormalities or following sustained
physical efforts.
- Secondary DVT include venous catheter- and devices-
related complications, cancer, pregnancy, and recent
arm/shoulder surgery or trauma. Most common clinical
presentation includes pain, swelling, and skin discoloration.
- Venous ultrasound (VUS) è first choice exam for
diagnosis.
- Anticoagulation is similar to that of lower limb DVT.
- Thrombolysis is not routinely recommended but limited to selected severe cases.
DVT at unusual sites
Cerebral vein thrombosis
Most common cerebral vein thrombosis (CVT) presentation includes severe headaches, seizures, focal neurological deficits, and altered
consciousness.
Splanchnic vein thrombosis
Splanchnic vein thrombosis may present as sudden onset of abdominal pain with or without other non-specific abdominal symptoms. Upper
gastrointestinal bleeding or abrupt ascites worsening may occur in cirrhotic patients, lower gastrointestinal bleeding, or acute abdomen may occur
in patients with mesenteric vein thrombosis.

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 DVT and cancer
- Cancer patients è 4-7- fold increased VTE risk (second cause of death). Incidental
VTE is increasingly diagnosed and associated with worse overall survival.
- VTE risk varies from cancer diagnosis through treatment, with annual incidence rate
of 0.5– 20% according to cancer site and type, metastasis status, treatment (surgery,
chemotherapy), use of central venous catheters, hospitalization, and patient-related
factor.
- Risk-assessment models may help stratify individual VTE risk and tailor adequate
therapy.

DVT in pregnancy
VTE è leading cause of maternal mortality.
VUS è primary imaging test.
LMWH è safe in pregnancy.
Anticoagulation should be continued for at least 6 weeks postnatally and until at least a total of 3
months treatment.

Consensus statement: DVT management in special situations:

- In case of UEDVT suspicion, venous US is the first choice imaging test.
- Treatment of UEDVT is similar to that of lower limb DVT with regard to anticoagulation.
- LMWH are recommended for acute treatment of CVT.
- LMWH are recommended for acute treatment of splanchnic vein thrombosis.
- LMWH are recommended for initial and long-term treatment in cancer patients.
- In cancer patients, after 6 months, decision of continuation and, if so, the mode of anticoagulation should be based on individual
evaluation of the benefit-risk ratio, tolerability, patients’ preference, and cancer activity.
- During pregnancy, venous US is recommended as first line DVT imaging test.
- During pregnancy, LMWH is recommended for initial and long- term treatment.
- Anticoagulant treatment should be continued for at least 6 weeks after delivery with a total of 3-months treatment.

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 Prevention and PTS is the most frequent chronic DVT complication, occurring in 30– 50% of patients within 2years after proximal DVT.
management of In 5–10% of cases, PTS is severe.
post thrombotic The Villalta score is the most used tool for diagnosis and treatment evaluation.
syndrome For decades, elastic compression stocking has been the mainstay for PTS management.
Management of Heparin è Protamin
bleeding during VKA è vitamin K
anticoagulation NOAC è idarucizumab (for dabigatran)

Follow up Development of conditions requiring anticoagulation adjustment should be monitored (e.g. renal insufficiency, pregnancy, weight loss, severe
hypertension).
Development of PTS should be evaluated. Venous US assessment, prior to anticoagulation discontinuation, is useful in determining baseline residual
vein thrombosis not to drive anticoagulant . treatment duration, but to differentiate between old and new thrombosis in case of new symptoms.
Following anticoagulation discontinuation, information should be given regarding future high thrombotic risk situations.
While on anticoagulation a yearly assessment is indicated.

Referensi:
1. Mazzolai, Lucia, et al. "Second consensus document on diagnosis and management of acute deep vein thrombosis: updated document elaborated by the
ESC Working Group on aorta and peripheral vascular diseases and the ESC Working Group on pulmonary circulation and right ventricular function." European
Journal of Preventive Cardiology (2021).
2. Mazzolai, Lucia, et al. "Diagnosis and management of acute deep vein thrombosis: a joint consensus document from the European society of cardiology
working groups of aorta and peripheral vascular disease and pulmonary circulation and right ventricular function”. European heart journal (2018).
3. Stone, Jonathan, et al. "Deep vein thrombosis: pathogenesis, diagnosis, and medical management." Cardiovascular diagnosis and therapy 7.Suppl 3 (2017):
S276.

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4. https://www.chegg.com/homework-help/heparin-protocol-dvt-pe-high-intensity-indications-goal-aptt-chapter-17-problem-13ua-solution-
9780073513805-exc

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