Thrombosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

To view main article on venous thrombosis, click here

To view main article on arterial thrombosis, click here for myocardial thrombosis or here for ischemic stroke

Overview

Thrombosis is the formation of a thrombus (medical term for a clot) inside a blood vessel. This can dislodge from the site it was formed and can move along the flow of blood to distant places in the body. A piece of thrombus that is transported in this way is called an embolus (plural emboli). This process of formation an emboli, from a thrombus is called thromboembolism. The term was coined in 1848 by Rudolph Carl Virchow.

The most important sites of thrombosis formation, based on their frequency and clinical effect are coronary arteries and deep veins of the legs. Former, the most important site of arterial thrombosis and latter the most important site of venous thrombosis.

Pathophysiology

Rudolf Virchow noted several factors affecting the clot formation, which are as follows:

1) Alterations in blood flow (stasis): Blood flows throughout the circulatory system, without significantly stopping or slowing any where. In certain pathological conditions where the blood flow slows down or stops, it causes:

• Increase in platelet to endothelium contact
• Decrease the dilution of clotting factors

This increases the risk of clot formation and form microthrombi, which further grow and propagate.

2) Injury to the vascular endothelium: Intrinsic or secondary to external trauma (eg, catheterization) can cause intimal damage and stimulates clot formation. See Coagulation.

3) Alterations in the constitution of blood (hypercoagulability): It is the propensity to develop thrombosis due to an abnormality in the system of coagulation.

These three conditions are collectively known as Virchow's triad and lead to intravascular coagulation, forming a mass of red blood cells, leukocytes, and fibrin.

Shown below is a table depicting the elements of Virchow's triad and their modern counterparts.

Virchow's	Modern	Notes
Phenomena of interrupted blood-flow	"Stasis" or "venous stasis"	The first category, alterations in normal blood flow, refers to several situations. These include turbulence, stasis, mitral stenosis, and varicose veins. The equivalence of Virchow's version and the modern version has been disputed.
Phenomena associated with irritation of the vessel and its vicinity	"Endothelial injury" or "vessel wall injury"	The second category, injuries and/or trauma to endothelium includes damage to the veins arising from shear stress or hypertension.
Phenomena of blood-coagulation	"Hypercoagulability"	The last category, alterations in the constitution of blood, has numerous possible risk factors such as hyperviscosity, deficiency of antithrombin III, nephrotic syndrome, changes after severe trauma or burn, disseminated cancer, late pregnancy and delivery, race, age, whether the patient is a smoker, and obesity. All of these risk factors lead to hypercoagulability.

Thrombus Formation

• Usually there is a balance between the coagulation and fibrinolysis systems in order to not having abnormal thrombosis in the body.
• Factors that increase the risk for a homeostatic imbalance include:

Thrombophilia

Immobilization

Trauma

• An insult to homeostatic balance can expose the sub-endothelium and lead to the collection of various coagulation factors. Accumulation of coagulation factors can lead to the formation of a thrombus of red blood cells, leukocytes, and fibrin.
• A thrombus is characteristically found to first develop in the calf veins and progressively grow in the direction of blood flow (leading to the heart).
• An exceedingly extensive thrombosis in deep veins can extend well into the iliac veins or the inferior vena cava.
• Atherosclerosis is a miss balance between lipids and the hemostasis system which caused clot in arteries. By occluding the artery myocardial infarction, stroke could happen .
• Thrombosis can happen in both Bare Metal Stent (BMS) and Drug Eluting Stent (DES).

Factors that serve as nidus for development stent thrombosis are:

Delayed endothelialization.

Inflammatory response to the stent material.

Hypersensitivity reaction around the stent material in DES serving as nidus for ST.

• Pregnancy increases risk of having thrombosis in both veins and arteries because of hypercoagulate state .
• Acquired risk factors for thrombosis are:

Oral contraceptive use,

Hormone replacement therapy

Advanced age

Surgery

Prolonged immobilization like hospitalization .

This video explains the process of thrombosis:

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Genetics

Genetic factors that play roles in causing thrombosis :

• Non-O blood groups
• Factor V Leiden mutation
• Prothrombin G20210A gene variants
• Polymorphisms in factors IX17 or XI

Gross Pathology

• Dull appearance.
• Zahn line from platelets and fibrin with layers of RBCs in pulmonary venous thromboembolism.
• Gross picture of thrombosis is different in live and dead person.

In live person it is gray and firm.

In dead person it is dark purple or yellow elastic called "chicken fat".

Microscopic Pathology

• lamination
• Zahn line

Classification

There are two distinct forms of thrombosis:

Venous Thrombosis

Main article: Venous thrombosis

• Deep venous thrombosis (with or without pulmonary embolism; together classified as venous thromboembolism/VTE)
• Portal vein thrombosis
• Renal vein thrombosis
• hepatic vein thrombosis (Budd-Chiari syndrome)
• Paget-Schroetter disease
• Cerebral venous sinus thrombosis
• Thoracic outlet syndrome (the cause of most Subclavian vein thrombosis unrelated to trauma)

Arterial Thrombosis

• Stroke
• Myocardial infarction
• Thoracic outlet syndrome

Classification of Embolism Based on Direction of Blood Flow

If a bacterial infection is present at the site of thrombosis, the thrombus may break down, spreading particles of infected material throughout the circulatory system (pyemia, septic embolus) and setting up metastatic abscesses wherever they come to rest.

Without an infection, the thrombus may become detached and enter circulation as an embolus, finally lodging in and completely obstructing a blood vessel (an infarction). The effects of an infarction depend on where it occurs.

The pathway of the embolism can be one of three types:

• Anterograde
• Retrograde
• Paradoxical

In anterograde embolism, the movement of emboli is in the direction of blood flow. In retrograde embolism, however, the emboli move in opposition to the blood flow direction; this is usually significant only in blood vessels with low pressure (veins) or with emboli of high weight. In paradoxical embolism, also known as crossed embolism, an embolus from the veins crosses to the arterial blood system. This is generally found only with heart problems such as septal defects between the atria or ventricles.

Causes

Thrombosis is caused by abnormalities in one or more of the following (Virchow's triad): the composition of the blood (hypercoagulability or thrombophilia), quality of the vessel wall (endothelial cell injury), and/or nature of the blood flow (stasis, turbulence)

Life Threatening Causes

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.

• Abruptio placentae
• Aortic dissection
• Disseminated intravascular coagulation
• Eclampsia

Common Causes

• Atherosclerosis

Causes by Organ System

Cardiovascular	Antithrombin III deficiency, aortic dissection, arteritis, atheroma, atherosclerosis, atrial fibrillation, atrioventricular septal defect, cholesterol embolization, congestive heart failure, coronary artery thrombosis, deep vein thrombosis, defibrination syndrome, disseminated intravascular coagulation, Eisenmenger syndrome, elevated lipoprotein a, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, Kawasaki disease, left ventricular failure, mesenteric venous thrombosis, obesity, Paget-Schroetter disease, pelvic vein thrombosis, peripheral vascular disease, plasminogen deficiency type I, plasminogen deficiency type II, postphlebitic syndrome, presence of a central venous catheter, stent, stroke, subclavian vein thrombosis, superficial thrombophlebitis, superior vena cava syndrome, vasculitis
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	Behcet's disease, Klippel Trenaunay syndrome, vasculitis
Drug Side Effect	Aflibercept, Asparaginase Erwinia chrysanthemi, asparaginase, chemotherapy, coagulation factor IX, coagulation factor XIII A-subunit, conestat alfa, desmopressin, elspar, eltrombopag, estramustine, estrogen replacement therapy, ethynodiol diacetate and ethinyl estradiol, femara, glucocorticoids, hormone replacement therapy, iodixanol, lenalidomide, letrozole, leunase, meclofenamate, oral contraceptives, pegaspargase, rapamune, romiplostim,sirolimus, tamoxifen, thalidomide, tromethamine
Ear Nose Throat	Mastoiditis, superior vena cava syndrome
Endocrine	Diabetes mellitus, obesity
Environmental	No underlying causes
Gastroenterologic	Budd-Chiari syndrome, chronic pancreatitis, hemorrhoids, hepatic vein thrombosis, inflammatory bowel disease, liver cirrhosis, liver disease, mucormycosis, obesity, pancreatic cancer, zygomycosis
Genetic	Ales dysfibrinogenemia, elevated plasma fibronectin levels, factor V Leiden mutation, Marchiafava-Micheli disease, paroxysmal nocturnal hemoglobinuria
Hematologic	Ales dysfibrinogenemia, antiphospholipid syndrome, antithrombin III deficiency, cavernous sinus thrombosis, decreased heparin cofactor II, decreased thrombomodulin, decreased tissue factor pathway inhibitor (TFPI), decreased tissue plasminogen activator deficiency, deep vein thrombosis, defibrination syndrome, disseminated intravascular coagulation, dysfibrinogenemia, elevated fibrinogen, elevated plasma fibronectin levels, elevated thrombin-activatable fibrinolysis inhibitor (TAFI), essential thrombocythemia, factor XII deficiency, heparin-induced thrombocytopenia, hypercoagulability syndrome, hyperviscosity syndrome, increased factor IX, increased factor VII, increased factor VIII, increased factor XI, increased plasminogen activator inhibitor-1 (PAI-1), Klippel Trenaunay syndrome, leukostasis syndrome, Marchiafava-Micheli disease, multiple myeloma, myeloproliferative disorders, Osler-Vaquez disease, Paget-Schroetter disease, paroxysmal nocturnal hemoglobinuria, pelvic vein thrombosis, plasminogen deficiency type I, plasminogen deficiency type II, polycythemia vera, polycythemia, postphlebitic syndrome, protein C deficiency, protein S deficiency, prothrombin gene mutation, sickle cell disease, sticky platelet syndrome, superior vena cava syndrome, thrombophilia, thrombotic microangiopathy, Von Willebrand factor, Waldenstrom macroglobulinemia, Wiesbaden dysfibrinogenemia
Iatrogenic	No underlying causes
Infectious Disease	Mastoiditis, meningococcal meningitis, mucormycosis, nipah virus encephalitis, sepsis, zygomycosis
Musculoskeletal/Orthopedic	Arthroscopy, fracture, hip surgery, immobility, knee surgery, Maffucci syndrome, orthopedic surgery
Neurologic	Antiphospholipid syndrome, cavernous sinus thrombosis, cerebral venous sinus thrombosis, idiopathic intracranial hypertension, meningococcal meningitis, nipah virus encephalitis, stroke, thoracic inlet syndrome, thoracic outlet syndrome
Nutritional/Metabolic	Elevated lipoprotein a, glycosylphosphatidylinositol deficiency, homocystinemia, hyperhomocysteinemia, hyperlipidemia, hypertriglyceridemia, obesity
Obstetric/Gynecologic	Abruptio placentae, antiphospholipid syndrome, eclampsia, leiomyoma, pre-eclampsia, pregnancy
Oncologic	Cancer, leukemia, Maffucci syndrome, malignancy, multiple myeloma, myeloproliferative disorders, Osler-Vaquez disease, pancreatic cancer, paraneoplastic syndrome, polycythemia vera, superior vena cava syndrome, Waldenstrom macroglobulinemia
Ophthalmologic	Retinal artery thrombosis, retinal vein thrombosis
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	Acute kidney injury, chronic renal disease, nephrotic syndrome, renal vein thrombosis
Rheumatology/Immunology/Allergy	Antiphospholipid syndrome, Behcet's disease, elevated interleukin 8, Klippel Trenaunay syndrome, polyarteritis nodosa, vasculitis
Sexual	No underlying causes
Trauma	Trauma
Urologic	Fournier gangrene
Miscellaneous	General surgery, high altitude, radiation, smoking, varicose veins

Causes in Alphabetical Order

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Differential Diagnosis

General Differential Diagnosis of Clotting Disorders Leading to Thrombosis

The following disorders might lead to thrombus formation in the coronary, pulmonary and peripheral circulation. The should be differentiated from each other:

Diseases	Clinical manifestations						Para-clinical findings				Gold standard	Additional findings
	Symptoms			Physical examination
							Lab Findings		Imaging
	Symptoms of DVT	Symptoms of Pulmonary Embolism	Symptoms of Myocardial Infarction	Tenderness in extremities	Edema in extremities	Warmth in extremities	PT	aPTT	Doppler ultrasound	Chest CT scan
Antithrombin deficiency	+	+	-	+	+	+	Normal	Normal Reduces the Increase in PTT after administration of heparin	Evidence of deep vein thrombosis (DVT) Should be used for diagnosis and follow up	Occlusion of brachiocephalic vein Large thrombus in superior vena cava	Decreased plasma antithrombin (AT III) activity	Nephrotic syndrome Decreased inhibition of factor II and Xa Antithrombin is a natural anticoagulant that is lost in the urine
Factor V Leiden mutation	+	+	+	+	+	+	N/A	↑	Recommended to do weekly Proximal DVT is more commonly observed as compared to distal DVT	Pulmonary embolism	N/A	Inactivates factor Va and factor VIIIa
Protein C deficiency	+	+	-	+	+	+	Normal	Normal / ↑	Hypercoagulation Recurrent venous thromboembolism	Venous thromboembolism Pulmonary embolism	Protein C functional assay ELISA assay: may produce false positive result in cross reaction with rheumatoid factor	Factor VIII elevation in acute phase Functional assay should not be performed if patient is on warfarin Purpura fulminans (skin necrosis) could be a form of presentation Risk of thrombotic skin necrosis following warfarin administration
Protein S deficiency	+	+	-	+	+	+	Normal	Normal / ↑	Hypercoagulation Recurrent venous thromboembolism	Pulmonary embolism Thrombosis of superior mesenteric vein	Protein S free antigen assay	When performing the gold standard test, beware of interference from samples positive for Factor V mutation, protein C deficiency and oral anticoagulants (rivaroxaban) Risk of thrombotic skin necrosis following warfarin administration Suspected in patients with a strong family history of VTE Post phlebitic syndrome Fetal loss
Prothrombin gene mutation	+	+	-	+	+	+	↑	N/A	Proximal DVT is more commonly observed as compared to distal DVT	Pulmonary embolism	Detection of mutation using restriction enzyme and PCR DNA testing for prothrombin G20210A mutation	Mutation causes increased production of prothrombin Increased blood levels of prothrombin lead to venous clots in the circulatory system Hormonal oral contraceptive pills can increase the risk of VTE
Disseminated intravascular coagulation (DIC)	+	+	+/-	+	+	+	↑	↑	Portal vein thrombosis is observed in patients with coexistent hepatitis B	Pulmonary embolism	N/A	Elevated fibrin degradation products (D-dimers) Decreased fibrinogen Decreased factor V and VIII Shistocytes (helmet cells) on peripheral blood smear Portal vein thrombosis
Antiphospholipid antibody syndrome	+	+	+/-	+	+	+	N/A	↑	Increased impedance of flow in uterine arteries at 12-20 weeks of gestation	Pulmonary embolism	Antiphospholipid antibody Anticardiolipin antibody Lupus anticoagulant Anti-β2GPI antibody	Both, arterial and venous thrombosis can occur History of spontaneous abortions False positive VDRL Stroke and transient ischemic attack (TIA) are most common forms of presentation of arterial thrombosis

Risk Factors

The following are the risk factors for thrombosis:

• General
  • Older age
  • Female gender
  • Smoking
  • Obesity
  • Pregnancy
  • Immobilization

• Medical
  • Surgery
  • Heart failure
  • Trauma
  • Oral contraceptive use
  • Varicose veins
  • Malignancy
  • Kidney disorders
  • Lupus anticoagulant
  • Paroxysmal nocturnal hemoglobinuria
  • Inflammatory bowel disease
  • Thromboangiitis obliterans
  • Disseminated intravascular coagulation

• Familial
  • Antithrombin III deficiency
  • Protein C deficiency/Protein S deficiency
  • APC resistance (Factor V Leiden)
  • Dysfibrogenemia
  • Hypoplasminogenemia
  • Familial homocysteinemia

Related Chapters

• Deep vein thrombosis
• Pulmonary embolism
• Anticoagulants
• Congestive heart failure and thrombosis
• Thrombolysis
• Thrombectomy