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Thrombosis is defined as the formation of a blood clot (thrombus) within a blood vessel (vein, artery) resulting from the adhesion of shaped blood components assisted by coagulation factors (figure 1). This specific mechanism is triggered whenever there is an exogenous vascular trauma (e.g. skin cut) and protects the body from bleeding. On the contrary, when the formation of a clot occurs intravascularly, it always conceals a pathological process and poses a risk to the limb/organ or even to the patient’s life.

An intravascular clot (venous or arterial) causes occlusion of the vessel and interruption of normal blood circulation, with a risk to the viability of the organ or limb. The formed thrombus can break off and cause an embolism, i.e. blockage in another area. A typical example is venous thrombosis of the lower extremities in which a thrombus can break off and cause a pulmonary embolism, a condition with high mortality and morbidity.

Figure 1 . femoral vein thrombosis

In 1856, the German pathologist Rudolf Virchow (1821-1902, Figure 2) first analyzed the pathophysiology of thrombosis by associating it with three individual factors (Virchow’s triad, 1) blood stasis, 2) endothelial damage and 3) hypercoagulability Table 1), arguing that for intravascular thrombosis to occur, one or more of the 3 factors of the triad must necessarily be present. The more of the above factors coexist simultaneously, the greater the likelihood of thrombosis occurring.

Table 1: Etiology of thrombosis (VIrchow’s triad)

1) stasis in blood flow – reduced flow velocity

Venous insufficiency with varicose veins

Immobility, bed rest, paralysis (postoperative period, splints, long air. trips)

Mitral stenosis, atrial fibrillation, heart failure

Ext. pressure on the vein from a mass/space-occluding lesion (pregnancy, cancer, cyst, etc.)

Obesity

2) damage or injury to the endothelium

Phlebotomy, arteriotomy

Endoluminal procedures, surgical procedures

Metal implants, stents, grafts, pacemakers, intravenous catheters

Chemical trauma from drugs (antineoplastics, chemotherapy)

Arteriosclerosis

Tumor infiltration

Microbial trauma to the endothelium

Smoking

3) blood hypercoagulability with the main representative being thrombophilias

thrombophilias

Cancer

Pregnancy, childbirth, puerperium

Estrogen preparations (contraceptives)

Nephrotic syndrome

Inflammatory disease, autoimmune diseases

Polycytemia, myelodysplastic syndromes

sepsis

Thrombophilia or hypercoagulable state is the tendency to form clots within the vessels. The term includes many pathological conditions, hereditary or acquired, characterized by the production of pathological coagulation factors, causing activation of the coagulation mechanism (Table 2).

Table 2: Thrombophilias

A) Acquired thrombophilias

Antiphospholipid syndrome including-lupus anticoagulant (LA) or anticardiolipin antibodies (IgG, IgM) or antibodies against glycoprotein Ia (antib2GPIa) (IgG, IgM)

Cancer, myelodysplastic syndromes, polycythemia

HIT (heparin-induced thrombocytopenia)

Autoimmune diseases

B) Inherited thrombophilias

Protein C deficiency

Protein S deficiency,

Antithrombin III deficiency

prothrombin G20210A – gene mutation

factor V-Leiden (G1691A and R2, H1299R) – gene mutation

Hyperhomocysteinemia from MTHFR gene mutation (C677T, A1298C)

Dysinogenemia

C) Mixed

Hyperhomocysteinemia

High fibrinogen (Inflammation, Tumors, Burn, Nephrotic Syndrome, Drugs, Pregnancy, Smoking)

Increased Factor VIII, IX, XI

Resistance to Activated Protein C

Both thrombosis and pulmonary embolism are now easily diagnosed based on simple tests. Clinical examination and history raise suspicion and follow with ultrasound – triplex veins for venous thrombosis (Figure 1) and chest CT scan for pulmonary embolism. Finally, the Dimers in the blood are a complementary but essential test since a negative value excludes thromboembolism.

In recent years, it has been proven that a significant percentage of individuals who develop thrombosis either have a hereditary predisposition, or they are part of an acquired syndrome. This percentage amounts to 50% in thrombosis episodes without another obvious cause (especially in young individuals). Patients with thrombophilia may manifest arterial or venous thrombosis (Table 3) or both types (stroke, myocardial infarction, deep vein thrombosis). or thrombosis, pulmonary embolism, pregnancy complications). Particularly in pregnancy, these thrombophilic states are responsible for complications such as: first trimester miscarriages, preeclampsia, fetal growth retardation, placental abruption and fetal death. Thrombophilias are divided into high-risk for thrombosis (Protein C, S, antithrombin III deficiency, HIT, antiphospholipid syndrome) and low-risk (Factor V-Leiden, prothrombin G20210A, Hyperhomocysteinemia, dysfibrinogenemia and increased factor VIII, IX, XI). In addition, they may be common, such as the presence of factor V Leiden, or rare, such as antithrombin III deficiency. It is worth noting that thrombophilias are “modern diseases” since the first (antithrombin III deficiency) was identified in 1965, while the most common abnormalities (including factor V Leiden) were described in the 1990s. Therefore, in cases where thrombosis is diagnosed, mainly of an atypical location, but the existence of a thrombophilic factor is not proven and of course in the absence of a classic cause of thrombosis (e.g. immobility, surgery, cancer), it is likely that there is a thrombophilic factor that has not yet been recognized and identified. Antiphospholipid syndrome (Table 2) has been shown to be one of the most dangerous thrombophilias, causing arterial or venous thrombosis at a very high rate, as well as miscarriages during pregnancy. Furthermore, its thrombosis is often in atypical locations (portal vein, mesenteric vessels, splenic, subclavian and cerebral veins).

Table 3: What type of thrombosis does each thrombophilia cause

Arterial thrombosis

Mixed thrombosis

Venous thrombosis

High fibrinogen

Hyperhomocysteinemia

Protein C deficiency

Arteriosclerosis

HIT

Protein S deficiency,

lipoprotein α

Antiphospholipid syndrome

Antithrombin III deficiency

prothrombin G20210A

factor V-Leiden

dysinogenemia

Increased factor VIII, IX, XI

Today we can diagnose many of the existing thrombophilias and treat them, preventing new episodes of thrombosis and embolism. Table 4 shows the classic test we give for the control of atypical thrombosis and suspected thrombophilia. The treatment includes the administration of anticoagulant drugs and selectively elastic compression with a stocking on venous thrombosis of the lower limb. In addition, the cause of secondary thrombophilia is treated. The anticoagulants we administer are oral (vitamin K antagonists such as sintrom, anti Xa factor such as rivaroxaban-abixaban-edoxaban, anti II factor such as dabigatran, antiplatelet agents such as aspirin-clopidogrel-prasugrel-integrelin, etc.) and injectable (basically anti Xa factor – low molecular weight heparin). With so many modern preparations and diagnostic tools at our disposal, we are able to treat the majority of thrombosis episodes, as long as patients seek timely medical attention. In addition, in the first hours after the thrombosis episode (and also in severe pulmonary embolism), systemic thrombolysis has a good effect in dissolving the clot and thus avoiding chronic post-thrombotic syndrome that causes leg edema and chronic pulmonary heart. Similarly, in chronic post-thrombotic syndrome, in recent years we have been applying balloon and stent techniques, and in acute/subacute pulmonary embolism, we use thrombus suction devices (Inari Medical flow Triever) with very good results.

Table 4. testing for atypical thrombosis with suspected thrombophilia

general blood tests

sugar, urea, creatinine, γGt, LDH, SGOT, SGPT, potassium, sodium, cholesterol, triglycerides, lipoprotein a, HDL/LDL, bilirubin, alkaline phosphatase

TKE, CRP quantitative

Cancer markers

PT, PTT, INR, clotting time, flow

Fibrinogen

DDimers

protein C, protein S, antithrombin III

a pcr (activated protein C resistance)

antinuclear antibodies (ANA)

lupus anticoagulant (LA)

anticardiolipin antibodies (IgG, IgM)

antibodies against glycoprotein Ia (antib2 GPIa IgG, IgM) C807T polymorphism

anti-glycoprotein IIIa (HPA-1 or antiGPIIIa) antibodies (IgG, IgM)

homocysteine

MTHFR (C677T, A1298C)

prothrombin G20210A

Factor V-Leiden (G1691A and R2, H1299R)