Deep venous thrombosis in patients with liver cirrhosis: Incidence and management

Deep venous thrombosis  in patients with liver cirrhosis: Incidence and management

Ahmed Saif Al-Islaml,MD; Mahmoud Saif Al-Isfam2,MD; Mohamed Zaki3MD

1) Vascular Surgery Department, Sohag University, Sohag, Egypt.

2) Tropical Medicine and Gastroentrology Department, Sohag University, Sohag, Egypt.

3) Diagnostic Radiology Department, Sohag University, Sohag, Egypt.

The purpose ofthis study is to investigate the incidence and predisposingfactors oflower limb deep venous thrombosis (DVT) in cirrhotic patients, and to evaluate the use of anticoagulation therapy (AT) with low molecular weight heparin (LMWH) and warfarin for managementofDVT in these patients. The study was conducted on 622 cirrhotic patients from whom the incidence of lower limb DVT was obtained. Six cirrhotic patients with lower limb DVT and twenty four cirrhotic controls were fully investigated  and compared. The patients and controls were age, sex and Child-Pugh  score matched. All the patients were assessed  according  to a protocol including prothrombin time, prothrombin concentration, international  normalized ratio (INR), protein C, proteinS, antithrombin III, serum bilirubin, serum albumin, platelet counts, HBs-Ag and HCV antibody. Results revealed that the prevalence of DVT in our cirrhotic patients was

0.96%. The use of AT in cirrhotic patients needs meticulous follow up for early management of any complications and the screening for esophageal varices with prophylactic band ligation if risk signs were present is of great importance.

Introduction:

Liver cirrhosis is accompanied by multiple changes  in  the  hemostatic  system  due  to the reduced levels of natural inhibitors of coagulation and coagulation  factors because of the impaired hepatic synthetic activity.l Thus, the global effect of liver disease on hemostasis is complex, and therefore, patients with liver cirrhosis  can experience  bleeding or thrombotic complications.2

Studies investigating the incidence of venous  thromboembolism   in  patients  with liver  cirrhosis  have  reported  a  risk  equal to3 or less than4 that of other medically ill hospitalized patients.

In severe  liver disease the  protein levels that are synthesized in the liver are reduced as the synthetic  capacity is lost. Thus, levels of both pro-and anticoagulant proteins decrease as   liver   disease   progresses.   A  relatively

balanced  reduction in pro-and anticoagulant

actlvtty does not result in a net hyper-or hypocoagulable state until the loss of liver synthetic capacity is severe. Local endothelial dysfunction can lead to the development of a hypercoagulable state and thrombosis.S

The  treatment  of  deep  vein  thrombosis and pulmonary embolism is well established and evidence-based guidelines are regularly updated. 6 Anticoagulant  therapy  in cirrhotic patients is complex because of an imbalance in hemostasis, as well as changes in the pharmacodynamics  of anticoagulants  in liver insufficiency.  Heparin   and  acenocoumarol have an average lifespan that is lengthened by their decreased metabolism; vitamin K deficit strengthens the action of acenocoumaroP

Aim of the work

The aim of this study is to know the incidence and predisposing factors of lower limb   deep   venous   thrombosis   (DVT)   in

Am-ShamsJSurg2014;7(2):363-368

cirrhotic  patients,  and  to  evaluate  the  use of anticoagulation  therapy (AT) with low molecular weight heparin (LMWH) and warfarin for management of DVT in these patients.

Patients:

This study was conducted on 622 cirrhotic patients who were admitted to Tropical Medicine  and Gastroenterology  Department in Sohag University Hospital from year 2007 to 2009. If a patient had multiple admissions during  the  study  period,  we  only  included the first admission during which abdominal ultrasound  and  lower  extremity  venous Duplex   ultrasound    was   performed.    The study included 2 groups.  Group 1 contained

6 cirrhotic patients with lower limb DVT. Group  2 contained  24 cirrhotic patients without  DVT enrolled  as cirrhotic  controls. The patients and controls were age, sex and Child-Pugh score matched.

Methods

Patients included in the study were given a clear explanation of the objectives and plan of  the  study  and  signed  informed  consent to  participate  in the  study. All the  patients and controls  were assessed  according  to the following protocol: age, gender, prothrombin time,prothrombin concentration, international normalized  ratio  (INR),  protein  C,  protein S, antithrombin III, serum bilirubin, serum albumin,   platelet   counts,   HBs-Ag,   Anti­ HCV and Child-Pugh score. Patients with diagnosis of lower limb DVT were evaluated for anticoagulation therapy.

Deep vein thrombosis  was detected using Duplex ultrasonography (Siemens Sonoline G50) on the venous system in the lower extremity.  The  Duplex  ultrasonographic criteria for DVT are as follows: no flow signal, direct clot visualization, loss of augmentation and incompressibility ofthe vein.s

For patients with lower limb DVT, esophagogastroduodenoscopy             (EGD) was done and prophylactic repeated band ligation   was  done  for   patients   with  risk signs  of  bleeding  and  a  beta  blocker  was given.   Then   LMWH   (enoxaparin,    1mg/

kg/d) in two divided doses was administered subcutaneously for five days followed by the vitamin   K  antagonists   warfaren   (Marivan

1mg tablet)  started  in the  last two  days  of

LMWH treatment  with a target prothrombin concentration  not  less  than  40%  and  INR of 2-3. Also, the patients received Diosnim (Dafton 500 mg tablet) twice daily and salt free albumin. The patients were followed  up twice weekly for 3 months by doing clinical evaluation, venous Duplex ultrasound examination, prothrombin concentration and INR.

Statistical analyses:

The data was analyzed by SPSS 10.0 software. Continuous data was expressed as mean ± SD,  while the  categorical  data was expressed as a number and percentage. The incidence of lower limb DVT in cirrhotic patients  was  calculated  from  the  total number of patients during the study period. Comparisons   of   differences   between   the two groups were performed by using the Student's t-test for the continuous data, while categorical data were compared by using the Fisher's  exact test. P values of less than 0.05 were considered significant.

Results:

Over two years, we included 622 cirrhotic patients, only 6 (0.96%) of them had lower limb DVTas diagnosed clinically by a swollen lower   limb   with   hotness   and  tenderness and confirmed by Duplex ultrasonography Figures (1,2). Hepatitis C was the most common underlying cause of liver cirrhosis found in 448 (72%) patients, followed by hepatitis B in 85 (14%) patients. 61 (10%) patients had negative serology but with past history of bilhariziasis,  22 (3%) patients had cryptogenic  cirrhosis,  and  6  (1%)  patients were alcoholic.

The  six  patients  with  lower  limb  DVT

received AT. Their mean age was 60.17 ± 4.17 years. Three  patients were Child-Pugh  class A, one patient was Child-Pugh class B, and 2 patients were Child-Pugh class C.

The   main   clinical   characteristics    and

laboratory  values  of cirrhotic  patients  with

Figure (1): Right common femoral vein (arrow) thrombosis in a 66 years patient with liver cirrhosis.

Figure (2): Right popliteal vein thrombosis in  a 56 years  patient with liver  cirrhosis. The image shows completely thrombosed popliteal vein (arrows).

Table(1): Clinical characteristicsand laboratory values of cirrhotic patients with and without

DVT.

and without DVT were compared. The results showed that only older age, diabetes mellitus, and history of lower limb orthopedic surgety were significantly more in cinhotic  patients with lower limb DVT. The coagulation profile showed a decrease in protein C, protein S, antithrombin III as a consequence of liver cinhosis. The two groups are age, sex, and Child-Pugh score matched with statistically insignificant difference in the levels of serum

albumin, prothrombin time and concentration, INR, platelet count, protein C, protein S, and antithrombin III Table(l).

When    the    diagnosis    of    lower    limb

DVT  was  made,  anticoagulation  therapy was struted in  4  patients and  delayed  for

3 weeks for the other 2 patients for whom EGO   revealed   1isky  esophageal   vmices and were subjected to endoscopic vruiceal band ligation. Owing  these 3 weeks the 2

patients   received   management in  the  form of bed rest, leg elevation  45°, and local medication  (thrombophobe gel).  After  3 months    of   AT,  one   patient    (Child-Pugh class A) showed  complete  recanalization of DVT, three   patients  (Child-Pugh class A,B) showed partial response, and two patients (Child-Pugh class  C) died during  the  follow up period because of liver decompensation (encephalopathy). Anticoagulation therapy was stopped after 3 months  whether  complete or partial recanalization was obtained. Fortunately no  patients  suffered  severe  side effects  of AT that  require  interruption of therapy.  Two patients  developed  anemia because  of  portal  hypertensive  gastropathy and received  fresh blood transfusion.

Discussion:

Several  mechanisms have  been  proposed to explain thrombosis in cirrhotic patients including, an acquired  deficiency  of  protein C, protein  S, and antithrombin IIJ.5,1,9

In  our  study  the  incidence of  DVT  was

0.96%.  Similar  results  were  reported  by Garcia-Fuster et  al,7 and  Northup  et  al,4  In our  study,  the  lower  limb  DVT  was  found only  in the right leg common and superficial femoral   and  popliteal   veins.  Also,  Garcia­ Fuster  et a1,7 observed that the right leg was more commonly affected.

We found   insignificant difference   in the

mean  prothrombin  time  and  concentration, and INR in cirrhotic patients with and without DVT. The studies conducted  by Northup et al, Garcia-Fuster et al, and Gulley et al, reinforces the  notion  that  the  perceived   coagulopathy in  patients   with  liver   disease,   as  reflected by prolonged INR values, does not protect patients  against venous thrombosis. 4,7,3

The  six  studied   patients   had  decreased levels of protein C, proteinS, and antithrombin III which  is mostly  acquired  due to  absence of prior thrombotic event before liver disease. These  patients   had  mean  albumin   value  of

2.8 ± 0.6 gm/dl with no significant  difference

when compared to the cirrhotic controls. In the study  by Ben Ari et al,lO and Northup  et al,4 the serum albumin level was independently associated with the occurrence ofthrombosis.

We did not find any association between protein   C,  protein  S,  and  antithrombin III, and the  development of lower  limb  DVT  in patients  with liver cirrhosis.  In liver cirrhosis the  concentrations of anticoagulant factors decrease   concomitantly  with   the   decrease in coagulation factors.  Decreased  natural anticoagulants, therefore, could not be considered  as  a  risk  factor  for  developing DVT.  There  were  many   other  risk  factors that  predispose to  DVT  such  as  age  above

60  years,  diabetes  mellitus,  and  lower  limb

orthopedic surgery.

Concerns exist  for  treating  cirrhotic patients as they are at risk ofbleeding because of coagulopathy and portal hypertension.ll ,l2

LMWH  was shown  to  be effective  and  safe in the treatment of PVT and other  vein thromboses in patients with liver cirrhosis.l3,6

Also, Garcia-Fuster et al,7 described the need for anticoagulation in treatment of lower limb DVT in patients  with liver cirrhosis.

Our   study   was   not    large   enough    to

evaluate  the safety of anticoagulation therapy in patients  with  liver  cirrhosis  but according to  our  management protocol   no  patient suffered  from  severe  side effects  of AT. This may be attributed to the continuous trials for improving the general condition ofthe patients by infusing  salt  free  albumin  and  correction of anemia by fresh blood transfusion. Also we screened the  patients  for esophageal varices and prophylactic band  ligation  was done  for two cases before the start of AT.

Despite    the     coagulation     dysfunction,

lower  limb  DVT could still occur  in patients with  liver  cirrhosis.  To  our  knowledge  our study is the first prospective study to evaluate the  incidence, predisposing factors  of lower limb  DVT  in cirrhotic  patients,  and evaluate the  use of  anticoagulation therapy  with  low molecular weight  heparin  and vitamin  K antagonist (warfarin) in  these   patients.  All the previous studies had limitation of being retrospective.

Conclusion

The  incidence of lower  limb  DVT  in our cirrhotic patients  was  0.96%.   Patients  with liver cirrhosis may share the same risk factors

for    DVT    as   other    non-cirrhotic   patients. The use of AT in cirrhotic patients needs meticulous follow up  for  early  management of any complication and screening for varices with  prophylactic band  ligation if risk  signs were  present.

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