Hypercoagulable States and the liver

By assistant lecturer: Waleed Fouad

PHISIOLOGICAL ASPECTS

Normal hemostasis • Comprises two equally important

processes: – Primary hemostasis.– Secondary hemostasis.

• While described as separate events, both primary and secondary hemostasis occur concurrently at a site of vascular injury.

Primary hemostasis

• It consists of three events that lead to the formation of a platelet "plug,"

namely:

– Platelet adhesion.– Platelet activation. – Platelet aggregation.

 

Secondary hemostasis

• It consists of a series of sequential reactions ("coagulation cascade") which consists of:

– Intrinsic pathway.– Extrinsic pathway.– Fibrinolytic pathway.

PCaXI

XIa

IXa

Xa

Thrombin

Fibrin

VIIIa PL

XIIa

PLVa

X

Prothrombin

Fibrinogen

Plasmin

IX

VIIa + TF

AT III

Extrinsic pathway

Intrinsic pathway

Physiologic fibrinolysis is initiated by endothelial-cell-derived tissue plasminogen activator (tPA)-mediated conversion of plasminogen to plasmin. Plasmin can

degrade both fibrinogen and fibrin, thus limiting the size of a thrombus and helping to clear a thrombus once the vascular injury has been repaired. The fibrinolytic

pathways are regulated by the inhibitory proteins alpha-2 antiplasmin and plasminogen activator inhibitor-1.

• This highly regulated hemostatic system maintains a delicate balance between a prohemorrhagic state and a prothrombotic state.

• This balance is maintained by the concomitant actions of: – Platelets, coagulation factors. – Fibrinolytic inhibitors (on one side of the

"hemostatic scale"). – Natural anticoagulants.– Fibrinolytic proteins (on the other side of

the scale)

Hypercoagulable states • These are group of inherited or acquired

conditions associated with a predisposition to:

• Venous thrombosis including: – Upper and lower extremity deep venous thrombosis.– Pulmonary embolism.– Cerebral vein thrombosis. – Intra-abdominal venous thromboses.

• Arterial thrombosis including: – Myocardial infarction.– Stroke.– Acute limb ischemia.– Splanchnic ischemia.

• Most hypercoagulable states alter the blood itself whereas others affect the vasculature directly.

• Not all persons with a well-defined hypercoagulable state will develop an overt thrombosis.

• Not all persons with thrombosis have an identifiable hypercoagulable state.

ETIOLOGYPrimary hypercoagulable states

• Include relatively rare inherited conditions that lead to defective endothelial cell thromboregulation.

Secondary hypercoagulable states

• It is seen in many heterogeneous disorders. • In many of these conditions, endothelial

activation by cytokines leads to loss of normal vessel-wall anticoagulant surface functions.

Primary hypercoagulable states

The major, inherited, inhibitor disease states include:

• Antithrombin III deficiency.• Protein C deficiency.• Protein S deficiency.

• Should be considered in patients who have recurrent, familial, or juvenile deep-vein thrombosis or occlusion in an unusual location such as a mesenteric, brachial, or cerebral vessel.

Other inherited Disorders

Factor V Leiden. Fibrinolytic abnormalities.Hypoplasminogenemia.Dysplasminogenemia.Dysfibrinogenemias.Tissue plasminogen activator release deficiency. Increased levels of plasminogen activator

inhibitor.Homocystinuria.Heparin cofactor II deficiency. Increased levels of histidine-rich glycoprotein.

• All inheritable causes has a genetic back ground.

• They present as recurrent familial thrombo- embolic disease.

• The initial thromboembolic event occurs after exposure to identifiable thrombosis risk factors pregnancy, – Postpartum complications.– Trauma.– Surgery.– Immobilization.– Oral contraceptives.

• Arterial thrombosis can occur.

Secondary hypercoagulable states

• Many Important clinical syndromes are associated with substantial thromboembolic events including:

– Antiphospholipid syndrome.– Heparin-induced thrombopathy. – Myeloproliferative syndromes.– Cancer.

Acquired antithrombin III deficiency

• It may be seen in various clinical settings including:

– Disseminated intravascular coagulation.– Liver disease.– Nephrotic syndrome.– L-asparaginase chemotherapy.– Oral contraceptive use.

Acquired deficiency of protein C or protein S or

both• It may be seen in:

– Severe liver disease.– Disseminated intravascular coagulation.– Nephrotic syndrome.– Acute respiratory distress syndrome.– Pregnancy.– Postoperative states.– After L-asparaginase therapy.– HIV (Decreases in protein S levels).

• C4b binding protein (an acute-phase reactant) binds protein S and may deplete the functional, free circulating protein S level.

• This may partly explain hypercoagulable states in association with acute inflammatory processes.

Recommended Laboratory Evaluation for Patients Suspected of Having an

Underlying Hypercoagulable State Screening Tests Confirmatory Tests

- Activated protein C resistance.- Prothrombin G20210A mutation testing by PCR. - Antithrombin, protein C, and protein S activity (functional) levels. - Factor VIII activity level.- Screening tests for lupus anticoagulants - Anticardiolipin antibody testing by ELISA. - Fasting total plasma homocysteine level.

1. - Factor V Leiden PCR 2. - Antigenic assays for

antithrombin, protein C, and/or protein S

3. - Confirmatory tests for lupus anticoagulants

HYPERCOAGULABLE STATES AND THE LIVER

• Hepatic hypercoagulable states can be encountered in:

– Budd-Chiari syndrome.– Veno-occlusive Hepatic Disease.– Portal vein thrombosis.– Hepatic artery thrombosis.

Budd-Chiari syndrome• Budd-Chiari syndrome is an uncommon condition

induced by thrombotic or nonthrombotic obstruction to hepatic venous outflow.

• Obstruction of intrahepatic veins leads to congestive hepatopathy.

• This results from obstruction of either large- or small-caliber veins, which leads to hepatic congestion as blood flows into, but not out of, the liver.

• Hepatocellular injury results from microvascular ischemia due to congestion.

• Portal hypertension and liver insufficiency result.

http://content.nejm.org/content/vol350/issue6/images/large/10t1.jpeg

Clinical variants

• Acute and subacute form: These are characterized by rapid development of abdominal pain, ascites, hepatomegaly, jaundice, and renal failure.

• Chronic form: This is the most common form of presentation. Patients present with progressive ascites. Jaundice is absent, and approximately 50% of patients also have renal impairment.

• Fulminant form: This form of presentation is uncommon. Fulminant or subfulminant hepatic failure is present along with ascites, tender hepatomegaly, jaundice, and renal failure.

Diagnosis

• Routine biochemical test are nonspecific. Mild elevations in serum AST, ALT, ALP are present in 25-50% of patients.

• Ascitic fluid analysis.– High protein concentrations (>2 g/dL).– WBC count is usually less than 500/mL.– Serum ascites–albumin gradient is usually less than 1.1.

• Hematological studies should be performed to evaluate for a hypercoagulable state.

• Imaging Studies– Ultrasound & Color-flow Doppler .– MRI scanning with pulsed sequencing.– Hepatic venography.

• Inferior venacavogram shows compression and lateral displacement of the IVC by an enlarged caudate lobe.

• Inferior venacavogram shows an upper IVC stenosis with reflux of the contrast into the hepatic venous circulation due to partial obstruction of the distal IVC.

• Wedged hepatic venogram shows a coarse-mesh spider web pattern resulting from an intrahepatic network of collateral vessels.

Management of the Budd–Chiari Syndrome (BCS).

Veno-occlusive Hepatic Disease

• The precise mechanism of this disease is still somewhat controversial.

• The central pathologic event in the development of VOD is development of vasculitis and nonspecific inflammatory changes in the vessel.

• This stimulates the deposition of fibrin in the portal vessels and results in decreased venous return in the liver.

• How the fibrin is activated and whether vascular wall thickening may cause sufficient obstruction are areas of controversy.

Etiology

• Coagulation inhibitor levels, such as PAI-1 and antithrombin III levels, are often depressed in hepatic VOD, thus, measurement of these levels may be helpful in distinguishing VOD from other disorders.

• Following preparative regimens containing busulfan.• Radiation to the liver.• Therapy with actinomycin D.• In the transplanted organ following liver and bone

marrow transplantation.• It has also been observed in other sites (e.g., mesentery,

colon) following both solid organ and bone marrow transplantation as well as conventional chemotherapy.

VOD tends to occur in 2 periods posttransplant

• Early VOD occurs in the first 2 weeks and is usually related directly to pretransplant risk factors and toxicities of the preparative regimen.

• Late VOD occurs a month posttransplant and may be influenced more by medications (cyclosporin) and infections in the posttransplant period.

DIAGNOSIS• The major clinical manifestations are jaundice,

painful hepatomegaly, weight gain, and ascites.

• In severe cases, multiorgan failure with pulmonary infiltrates, pleural effusions, congestive heart failure, and renal failure may occur.

• Many nonspecific U/S findings include ascites, gallbladder wall thickening, and hepatosplenomegaly.

• Doppler ultrasound may be helpful in some cases.

• The demonstration of normal portal venous flow prior to transplantation with flow reversal within 3 weeks after BMT is a highly suggestive but insensitive marker for VOD.

• Color Doppler demonstrates reversed (hepatofugal) flow within the portal vein.

• Pulse wave Doppler of selected branches demonstrate a normal flow pattern.

Therapy• Approaches to decreasing fibrin deposition with the use of heparin

have been tried with limited success.

• Approaches to increase fibrin degradation have been tried using low-dose tissue plasminogen activator (t-PA) and have also met with limited success.

• The combination of approaches has been tried with moderate success.

• The combination of antithrombin III and heparin/t-PA has become the most commonly used strategy, as of August 2000, no large-scale studies of these treatment approaches have been conducted.

• Definitive treatment recommendations, therefore, are not available.

Portal vein thrombosis

• Idiopathic causes • Hepatocellular

carcinoma • Cholangiocarcinoma • Pancreatic carcinoma • Gastric carcinoma • Trauma • Iatrogenic umbilical

vein catheterization • Abdominal sepsis • Pancreatitis• Perinatal omphalitis

• Appendicitis • Diverticulitis • Ascending cholangitis • Myeloproliferative disorders • Hypercoagulable

syndromes • Estrogen therapy • Severe dehydration • Cirrhosis, especially in the

young • Portal hypertension

Clinical formsAcute PVT• Patients can present emergently with sudden onset

of right upper quadrant pain, nausea, and/or fever.

• Alternatively, the symptoms of the primary infectious and inflammatory condition that led to PV obstruction predominate (eg, right lower quadrant pain in appendicitis).

• Progressive ascites, intestinal ischemia resulting from propagation of thrombus, or intestinal suffusion secondary to acute portal hypertension can also be the presenting manifestations.

• Occasionally, variceal bleeding can occur acutely with development of PVT, particularly in the setting of preexisting varices with cirrhosis.

• In the acute phase, the presentation of portal vein obstruction is relatively uncommon and easily missed because the patient may be asymptomatic.

• Symptoms most often begin in the chronic or subacute stage.

• Spontaneous resolution of acute/recent thrombosis undoubtedly occurs and symptoms abate.

• In other patients, the acute symptoms often subside as collaterals develop, and the diagnosis may be missed.

• These patients then present at a later stage with manifestations of portal hypertension.

Chronic PVT• These groups of patients most often present with

complications related to portal hypertension.

• In 90% of cases, variceal bleeding is the presenting complaint.

• On average, this occurs 4 years after the thrombotic event and has been described as long as 12 years later.

• Ascites is less frequent, and hepatic encephalopathy is rare in the absence of preexisting cirrhosis.

• In the presence of cirrhosis with underlying hepatic insufficiency, sudden worsening of hepatic function, development of hepatic encephalopathy, and development of ascites are all more frequent, leading to worse outcomes.

• With intra-abdominal malignancies, bleeding is less commonly the first manifestation because many of these patients do not survive long enough to develop sequelae of portal hypertension.

• These patients most often present with sudden ascites, anorexia, right upper quadrant or epigastric pain, and weight loss.

• Portal vein obstruction may also be discovered incidentally on imaging studies obtained for pain or ascites.

• Rarely, patients with portal vein obstruction present with a fever of unknown origin.

• Splenomegaly is found in 75-100% of patients, most presenting in the chronic stage.

• Stigmata of chronic liver disease, such as spider angiomata or palmar erythema, are usually found in the presence of underlying liver disease.

• The presence of caput medusae indicates posthepatic or intrahepatic portal hypertension.

• In children, growth retardation may be present.

• Abnormalities of the extrahepatic biliary tree may occur in 80% of cases due to compression by choledochal or periportal varices or from ischemic stricturing.

Diagnosis

• Liver function test results are only mildly elevated in the absence of underlying cirrhosis or massive hepatic malignancy.

• Hematological studies should be performed to evaluate for a hypercoagulable state.

• Imaging Studies:– Ultrasound & color Doppler.– MRI and MRA.– Contrast-enhanced CT scan.– Angiography. – Endoscopic ultrasound (EUS).

MRI Hepatocellular carcinoma with portal vein thrombosis.

• The short arrow indicates the tumor thrombus with an abrupt cut off of the portal vein.

• The long arrow points to a compensatory, prominent left hepatic arterial branch.

• The color Doppler sonography at the level of the porta hepatis shows the longitudinal image of the portal vein with the lumen filled with hyperechogenic material.

Therapy

• At least one-third of the PVT patients exhibit a combination of thrombotic risk factors.

• Treatment with anticoagulant drugs has not proved beneficial for most PVT patients.

• Therapy with anticoagulants is only recommended in those with: – Acute PVT. – After portosystemic shunt procedures. – Those with other thrombotic manifestations, particularly in

case of proved hypercoagulability.

• Anticoagulation in patients with acute/recent portal vein thrombosis, studied only retrospectively, has been shown to: – Recanalize in more than 80% of cases.– Prevent advancement of thrombosis or rethrombosis.

• Debate remains regarding the risk-to-benefit ratio of anticoagulation in chronic portal vein thrombosis and should be decided on a case-by-case approach at this time.

• Thrombolysis: This approach is recommended in acute portal vein thrombosis through the transhepatic route, which avoids the need for systemic thrombolysis.– Tissue-type plasminogen activator (tPA) has been used

for this purpose, followed by prolonged anticoagulation therapy with coumadin for at least 3 months (indefinitely in patients with inherited coagulation disorders).

Shunt surgery

• A distal splenorenal shunt is usually the preferred surgical shunt.

• A more recent salvage operation showing success is the right and left mesogonadal shunt.

• In patients who are critically ill, esophagogastrectomies have been used as a last resort.

• In the presence of cirrhosis, the operative mortality rate has been reported to be 18%.

• In the absence of cirrhosis, operative mortality is approximately 2%.

TIPS• Previously considered a relative contraindication in portal vein

thrombosis.

• Stent placement requires an aspiration thrombectomy through a sheath with subsequent angioplasty of the tract and stent placement.

• Some centers have obtained good results by performing an embolectomy and then using local thrombolytic therapy through the TIPS after deployment.

• In portal vein obstruction, TIPS is indicated in uncontrollable variceal bleeding in a patient with cirrhosis, usually as a bridge to transplant. TIPS has the advantage of being less invasive than shunt surgery.

Liver transplantation

• In patients referred for OLT, PVT complicates 5-15% of cases.

• Although traditionally viewed as a relative contraindication to OLT, recent innovative surgical techniques (eg, thrombectomy, venous jump grafts, use of portal vein tributaries) have resulted in improved results post-OLT.

• In patients with associated PVT, the 5- and 10-year survival rates after OLT are approximately 63% and 53%, respectively, whereas, in patients without thrombosis, the 5- and 10-year survival rates after OLT are 67% and 59%, respectively.

• In patients with associated PVT, a higher incidence (5%) of primary nonfunction, renal failure, and recurrent portal vein thrombosis exists.

HYPERCOAGULABLE STATES AND CIRRHOSIS

• Despite the endogenous coagulopathy of cirrhosis, some patients with cirrhosis experience thrombophilic states.

• Thrombosis is rare in compensated cirrhosis, which suggests that liver failure is an important factor.

• The pathogenesis of thrombosis in patients with cirrhosis is not known.

• Lupus anticoagulant has been reported in such patients but has not previously been evaluated as a risk factor for thrombosis.

• Plasma concentrations of antithrombin III, protein C, and protein S, which may be low in patients with cirrhosis, may also promote thrombosis.

• Low serum albumin was strongly predictive of increased risk for developing VTE, independent of international normalized ratio or platelet count.

• Serum albumin deficiency may indicate low levels of endogenous anticoagulants.

Precautions in cirrhotic patient with a

thromboembolic event• Avoid diuretic use Dehydration• Avoid colloid infusion.• Use low molecular weight heparin.• Follow the patient carefully for any

hemorrhagic tendency.• Very frequent monitoring of PT, PC

and INR.

Hepatic artery thrombosis• Hepatic artery thrombosis after liver transplantation is

uncommon, but represents an important cause of morbidity and mortality.

• This catastrophic event may result in hepatic gangrene and death unless prompt retransplantation is performed.

• Rejection probably plays a role in hepatic artery thrombosis in some cases.

• Thrombosis may be related to turbulent flow at difficult anastomoses.

• Hepatic artery thrombosis was diagnosed from 5 days to 3 months after transplantation.

Clinical Outcome• Clinically, hepatic artery thrombosis presents

in three forms with equal frequency.

• A second presentation is delayed biliary leak. – After transplantation, the donor bile duct is

entirely dependent on hepatic arterial blood supply, usually the right.

– Occlusion may result in bile-duct ischemia and necrosis.

• A third presentation is intermittent episodes of sepsis without an evident source, probably caused by focal abscesses within infarcted areas of the liver.

Diagnosis

• The patient often already has clinical toxic septicemia with marked elevations in serum transaminases.

• Noninvasive evaluation of hepatic artery blood flow is needed to detect occlusion of the hepatic artery before infarction occurs.

• Possible imaging techniques:– Visual detection of hepatic artery pulsation with real-time

sonography.– Dynamic intravenous CT scanning of the hepatic artery.– Radionuclide hepatic flow studies.– Intravenous digital subtraction angiography.

Diagnostic algorithm for radiologic evaluation of patient with suspected hepatic artery thrombosis after liver transplantation.

• Collateral circulation after hepatic artery thrombosis.

• Extensive arterial collaterals (arrows), which reconstitute intrahepatic arteries (arrowheads), are demonstrated on selective superior mesenteric arteriogram 2 months after transplant.

Managment

• The use of postoperative prophylactic anticoagulation therapy might be of benefit in the prevention of hepatic artery thrombosis after liver transplantation.

• All adult patients with complete arterial thrombosis ultimately require retransplant.

• The presence of collaterals has significant implications for survival and may minimize the need for retransplant.

• Although experience is still limited, placement of a stent in the hepatic artery in cases of thrombosis yields promising results enabling the graft to survive and avoiding the need for repeat transplantation.

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