Dardo Riveros

Hemorrhagic phenomena are controlled by the interaction between blood vessels, platelets, and a plasma protein system. Close collaboration between these three sectors tends to prevent blood loss from intact vessels and to inhibit excessive bleeding in injured vessels.

The coagulation mechanism comprises three phases: vascular, platelet, and plasma.

  1. Vascular phase.The entire vascular anatomy, including the endothelium, the basement membrane, the muscle fibers, and the perivascular connective tissue, participates as a whole in the mechanism of hemostasis when a vessel injury occurs. These structures provide support to the vascular tree through collagen of the basement membrane and adventitia, facilitate vasoconstriction by contraction of muscle fibers, and initiate the formation of the primary hemostatic plug by the adhesion of platelets to the collagen of the exposed subendothelium. In addition, they trigger the mechanism of the plasma coagulation phase by activating factors XII and VII, the first by contact with the basement membrane and the second by the invasion of tissue thromboplastin from the perivascular area. Finally, contribute to fibrinolysis by releasing plasminogen activator synthesized by endothelial cells. Vasoconstriction is mediated neurologically by the adrenergic system, and humorally by substances released locally by platelets, especially thromboxane A2, a platelet product of arachidonic acid metabolism. 
  1. Platelet phase. Exposure of subendothelial collagen caused by vascular injury leads to platelet stickiness (binding of platelets to non-platelet surfaces). The platelets thus adhered release ADP (adenosine diphosphate), which initiates the stage of platelet aggregation (binding of platelets to each other) and leads to the formation of a platelet "plug". Subsequently, the platelets have their factor 3 content and release it, causing the activation of the intrinsic coagulation mechanism, with consolidation of the platelet "plug" by fibrin and retraction of the clot.

In this way, the following stages can be recognized in the platelet phase: a) adhesion, b) release, c) aggregation, d) availability of factor 3 (F3) and e) retraction of the clot.

Adhesion involves a specific biochemical interaction between the platelet membrane and the structure of collagen or Ja elastin, also involving other factors such as some plasma proteins or the speed of blood flow.

In the release reaction, a large number of substances found in platelet organelles are discharged into the surrounding medium, standing out among them ADP, ATP, vasoactive amines and calcium ions. The intimate biochemical mechanism that initiates the release reaction is poorly understood, but it is known that it requires energy, which is obtained from the breakdown of ATP from metabolic platelet nucleotide deposition.

The released ADP, probably acting on specific receptors of the platelet membrane, produces a reversible primary aggregation with greater release of ADP, which, in turn, causes a second wave of irreversible type aggregation (secondary aggregation).

There is evidence that cAMP (cyclic adenosine monophosphate) levels are important in the aggregation phase: their increase produces a decrease in the aggregative response, probably due to redistribution of calcium in the platelet.

The binding of platelets to each other and to other surfaces initiates the availability of F3. This is a platelet lipoprotein that is used in at least two reactions of the intrinsic coagulation mechanism: the interaction between factor IXa and factor VIII, and between factor Xa and factor V. This will lead to the production of fibrin, which will reinforce the platelet plug.

Finally, retraction of the clot occurs due to the union of platelet thrombi to fibrin meshes, although other phenomena also intervene in this mechanism. 

  1. Plasma phase. It is carried out by the joint action of two groups of proteins: one of them leads to the formation of fibrin (coagulation system) and the other to its removal (fibrinolysis system). Both have activating and inhibiting proteins, which, under normal conditions, guarantee the correct balance of the hemostatic process. Clotting factors are synthesized in the liver, but it should be recognized that the site of factor VIII production is not yet fully characterized. In addition, the posribosomal action of vitamin K is necessary for factors II, VII, IX and X to be competent from the hemostatic point of view.

In the coagulation system two mechanisms are recognized that lead to the production of fibrin, the intrinsic and the extrinsic. They represent, from the biochemical point of view, a series of chain reactions through which a proenzyme is converted into an active enzymatic form by exposure of serine groups of its molecule. These activations continue until the conversion of fibrinogen to fibrin.

The intrinsic mechanism is activated with the activation of factor XII by contact with negatively charged surfaces (subendothelial collagen, for example), and includes the successive activation of factors XI, IX, VIII and X. For its part, the extrinsic pathway , faster than the previous one, is represented by the activation of factor VII in the presence of tissue thromboplasty material, which in turn will activate factor X. It can be seen that both mechanisms converge at the same point, the activation of factor X, from which the pathway is common until the formation of fibrin and its stabilization by the action of factor XIII. The activation of factor XII, in addition to initiating the intrinsic coagulation mechanism, also represents the link between it and other important protein systems of the body (complement, fibrinolysis and kallikreins). The fibrinolysis system maintains the permeability of the vascular tree through the digestion of fibrin by plasmin, which generates fibrin degradation products (PDF). Plasmin is formed from an inactive plasma precursor, plasminogen, by the action of plasminogen activators.

These activators can be of tissue or plasma origin, and are widely distributed in the endothelium, especially in the small veins. A plasminogen activator of renal origin, urokinase, is also recognized.

Table 53-1. Vascular abnormalities

  • Structural malformations
    • Hereditary:
      • Osteogénesis
      • Ehlers-Danlos syndrome
      • Marfan syndrome
      • Homocystinuria
      • Elastic pseudoxanthoma
      • Giant cavernous hemangioma
      • Hereditary hemorrhagic telangiectasia
    • Acquired:
      • Scurvy
      • Senile purple
      • Cushing's disease
      • Corticosteroid purpura
  • Dysproteinemic purples
    • Plasma cell dyscrasias
  • Immune vascular purples (vasculitis)
    • Crioglobulinemias
    • Collagenopathies
    • Schonlein-Henoch purpura
    • Bacterial infections (meningococcal, strep)
    • Drug effect
  • Others:
    • Bacterial and viral infections
    • Mechanical purple
    • Orthostatic purple
    • Associated with skin diseases:
    • Schamberg's disease
    • Angioma serpiginoso
    • Telangiectatic ring purple


Hemorrhagic manifestations are the clinical expression of quantitative and / or qualitative alterations of one or more of the sectors of the mechanism of hemostasis and fibrinolysis. The distinction between vascular, platelet and plasma abnormalities should not be considered rigidly since the same etiological agent can simultaneously modify several sectors, forming complex symptoms. 

  1. Vascular abnormalities. They constitute a heterogeneous group in which blood extravasation occurs due to lack of integrity of the vascular wall or poor vascular-platelet interaction. In some cases (Table 53-1) this is due to hereditary structural changes in the vessel wall or perivascular support tissue, linked to metabolic deficiencies or other unclear pathogenesis. In others, hemostatic failure is acquired and related to the deposit of abnormal proteins in the endothelium, or with vascular inflammatory processes triggered by immune mechanisms, or with lo constitutive deficits of the vascular wall or its supporting structures due to vitamin deficiency, old age or corticoid effect. 
  1. Piaquetary abnormalities.The adequate formation of the primary hemostatic plug depends fundamentally on the number of platelets and their functional state. Decreased number of circulating platelets, or thrombocytopenia, is the most common hematologic cause of bleeding, and may be the result of poor production, rapid destruction or utilization, or abnormal platelet distribution due to an enlarged spleen ( Table 53-2). Platelet functional disturbances can be acquired during the evolution of various diseases or be a consequence of the pharmacological action of some drugs, but congenital functional defects have also been described (Table 53-3). In almost all of them it has been possible to specify the stage of platelet function that is altered (adhesiveness, release reaction, aggregation or availability of F3). Some of the congenital forms are accompanied by other hemostasis defects: for example, thrombocytopenia in the Bemard-Soulier and Wiskott-AIdrich syndromes and variable alterations in the factor VIII molecule in von Willebrand disease. 
  1. Plasma abnormalities. Deficiency of one or more of the factors of the plasma coagulation phase is the cause of hemorrhagic disease. From the pathophysiological point of view, the decrease in the concentration or plasma activity of a factor may be the result of poor synthesis, faulty synthesis, accelerated use, or inactivation.

Poor synthesis:  In these cases there is a quantitative alteration, with a real decrease in the factor. This is evidenced by verifying a coincidence between the values ​​obtained by immunological methods (which measure the protein without taking into account its functional capacity) and those obtained by biological or functional techniques (which evaluate the coagulant quality of the protein).

The quantitative alteration of the factor is produced by a decrease in its synthesis, which may be genetically conditioned (hereditary afibrinogenemia, congenital deficits of factors V, XI or XII and von Willebrand disease) or be the product of an acquired pathology (acute liver disease and chronicles).

Defective synthesis:  These are qualitative alterations since the factor is in sufficient quantity, but it is incompetent from the hemostatic point of view. Therefore, there will be a dissociation between their plasma levels detected by immunological methods and those assessed by functional methods. There are congenital forms (hemophilia A, hemophilia B, congenital dysfibrinogenemia) and others acquired (dysfibrinogenemias acquired in liver diseases, vitamin K deficiencies).

In certain cases, the factor not only does not adequately fulfill its hemostatic function, but also exerts an inhibitory effect on the coagulation mechanism, as occurs with some abnormal fibrinogens.

Increased utilization or losses. When the mechanisms of coagulation or fibrinolysis are activated by some abnormal stimulus, a deficit of factors occurs due to consumption or use. If the stimulus is sufficiently powerful and long-lasting, the synthesis of factors cannot compensate for the use and severe and general bleeding can occur. Disseminated intravascular coagulation and primary fibrinolysis are examples of this mechanism. These tables represent intermediate pathophysiological processes that complicate the evolution of a wide variety of conditions (severe infections, burns, neoplasms, viper bites, etc.).

Inactivation: In collagenopathies, malignancies or due to the effect of drugs, antibodies can be produced that inactivate a coagulation factor or that neutralize a stage of this process. They are known as acquired hemostasis inhibitors and can also be found in healthy people. Almost all the factors and stages of hemostasis may be the target of an inhibitor, but the best known and most frequent are anti-VIII (in polytrafused hemophiliacs or healthy women during the puerperium) and antiprothrombinase (systemic lupus erythematosus and lymphomas). .

Table 53-2. Thrombocytopenias

  1. Poor production
    1. Hypoplasia or suppression of megakaryocytes:
      1. Aplastic anemia
      2. Physical and chemical agents (drugs, radiation)
      3. Bone marrow invasion (leukemias, metastasis)
      4. Congenital megakaryocytic hypoplasia
    2. Ineffective thrombopoiesis:
      1. Megaloblastic anemia
      2. Paroxysmal nocturnal hemoglobmuria
    3. Alterations in thrombopoietic control mechanisms:
      1. Cyclic thrombocytopenia
      2. Periodic platelet dysgenesis
    4. Hereditary forms:
      1. Bemard-Soulier syndrome
      2. Wiskott-AIdrich syndrome
  2. Destruction, loss or accelerated use
    1. Immune mechanism:
      1. By antibodies: "idiopathic" thrombocytopenic purpura, collagen diseases, lymphoproliferative syndromes, drugs
      2. By isoantibodies: post-transfusion purpura, fetomatemic incompatibility purpura
    2. Non-immunological mechanism:
      1. Thrombotic thrombocytopenic purpura
      2. Disseminated intravascular coagulation
      3. Cardiac valve prostheses.
      4. Extracorporeal circulation apparatus
      5. Some bacterial infections
  3. Abnormal distribution
    1. Spleen diseases (congestive, neoplastic, infectious, infiltrative)

Symptoms and signs of hemorrhagic diseases 

Obtaining a careful medical history can offer sufficient information to characterize a hemorrhagic manifestation as vascular, platelet or plasma origin. However, it must be recognized that in many situations this is not possible, and that laboratory tests should be used to clarify the diagnosis. 

The symptoms and signs of hemorrhagic diseases can be arbitrarily divided into two groups: those that are more frequent in vascular platelet disorders and those that are more common in disorders of plasma coagulation. The former are known by the descriptive name of "purpura", due to the predominance of cutaneous and mucous hemorrhages. 

To differentiate between the two groups, the following data must be t loaken into account (in addition to some more or less characteristic signs that will be discussed later): age and sex of the patient; family history of bleeding diathesis; previous responses to situations such as surgical interventions, dental extractions, trauma or superficial wounds; recent ingestion of medications; early or late onset of bleeding with respect to the moment of injury or trauma, and finally, coexistence of the bleeding phenomenon with another recognized disease (collagen or liver disease). 

The evaluation of this information will allow to distinguish with some precision the vascular, platelet and plasma alterations, in addition to their character of inherited or acquired.

Vasculoplatelet disorders (purple). The characteristic sign of these alterations is petechiae, a flat spot, purplish red, of small size (“pinhead”), which expresses an extravasation of red blood cells at the capillary level. Typically several appear in "buds" and are evident in places where clothing exerts greater pressure. In Cough vascular defects usually appear more frequently in the lower extremities, while in thrombocytopenias petechiae have a more general distribution, although this is not categorical. In scurvy they adopt a peripheral colonic location on the buttocks and thighs.

Petechiae must be differentiated from telangiectasias, angiomas, and vasculitic lesions. The first two, which can be observed in liver disease, pregnancy or hereditary hemorrhagic telangiectasia, are permanent and disappear due to pressure, features that distinguish them from petechiae. Furthermore, the telangiectasias of liver diseases can be slightly raised and have fine extensions (in “spider legs”). On the other hand, angiomas, although they do not disappear with pressure, differ from petechiae in that they are permanent and elevated or nodular. Vasculitis lesions, which can coexist with petechiae, are usually larger than these, are papular and are accompanied by inflammation and even dermal necrosis.

Another common sign in vascular platelet disorders is ecchymosis. These are dermal hemorrhages, greater than 3 mm, with irregular and confluent edges, and purplish in color at first, which then turns yellowish green. They are usually small and multiple, unlike those observed in plasma disorders, which are larger and solitary.

It is extremely rare to find hematomas (palpable hemorrhages, located between tissue planes) or hemarthrosis (hemorrhages in articular cavities) and its presence should suggest a plasma disorder (for example, hemophilia). In this regard, there are some vascular conditions that produce manifestations that require differentiation, such as subperiosteal bleeding in scurvy or synovitis in Schoniein-Henoch purpura.

Other data that allow us to distinguish purpuric from plasma changes are: early onset of bleeding in areas of superficial wounds, rarity of delayed bleeding in relation to the time of injury, relatively higher frequency in women, and an unusual finding of a positive family history .

Some signs may have prognostic significance, especially with regard to the imminence of bleeding at the level of the central nervous system: an example is the "onyalai" (vesicles with hemorrhagic content in the oral cavity) or hemorrhages in the fundus of eye seen in some thrombocytopenic purples.

Usually there is no pathognomonic clinical manifestation that allows differentiating between the different types of vascular and platelet disorders (Tables 53-1, 53-2 and 53-3); perhaps the only exceptions to this are hereditary hemorrhagic telangiectasia lesions (Rendu-Osler disease) and giant cavernous hemangioma. In other cases, associated clinical data or laboratory tests should be used to reach the diagnosis.

Associated clinical data. They rank the value of obtaining a careful and complete medical history. Some examples are: arachnodactyly and chest deformities in Marfan syndrome; hyperextensibility of skin and ligaments in Ehlers-Danios syndrome; alopecia, aryalgia or Raynaud's phenomenon in thrombocytopenia or vasculitis due to systemic lupus erythematosus; arthralgia and abdominal pain in Schonlein-Henoch purpura; ingestion of drugs that alter vascular or platelet behavior (corticosteroids, acetylsalicylic acid), etc.

Laboratory exams. Those that provide information on the status of the platelet vasculature stage (loop test, bleeding time, platelet count, prothrombin consumption, and clot retraction) are useful. In addition, there are other more complex tests that require a specialized laboratory: "in vitro" platelet function tests for qualitative platelet disorders; medullogram, platelet survival and platelet-associated immunoglobulins in thrombocytopenias; histological and chemical study of collagen and elastin in hereditary vascular abnormalities; histological and immunohistochemical study in vasculitis, etc.

Table 53-3. Qualitative platelet disorders



Function altered primarily


Glanzmann's thromboasthenia


Deposit Pool Disease



Factor 3 availability

Sindrome by Bernard-Soulier

Factor 3 availability

Wiskott-Aldrich syndrome

Multiples and variables


Multiples and variables

Congenital connective tissue diseases (Marfan, Ehlers-Danlos)

Adhesiveness to own collagen and release


Adhesiveness to own collagen and release

Von willebrand disease

Adhesiveness and aggregation with ristocetin



Drugs (acetylsalicylic acid)





Multiples and variables

Myeloproliferative syndromes

Multiples and variables



Plasma abnormalities. They are clinically distinguished from purples by the absence of petechiae, slight bleeding after superficial wounds, and the frequent appearance of bruising, extensive bruising, and hemarthrosis. Furthermore, they have the phenomenon of delayed bleeding and usually have a positive family history.

Blood loss at the level of different bodily orifices (metrorrhagia, hematuria, proctorrhagia, gingivorrhagia, and epistaxis) is found with similar frequency both in purples and in plasma coagulation disorders, and therefore does not allow their differentiation. Contrary to this * the presence of hemorrhages in serous cavities or in muscle sheaths, the existence of large hematomas of the orbit, bleeding in multiple venipuncture sites, or the coexistence of hemorrhagic and thromboembolic phenomena are indications of plasma coagulation alteration .

When coagulopathy of this origin is suspected, one must try to establish its congenital or acquired character, since this is an important piece of information to formulate the diagnostic impression.

Bleeding during the first month of life, with a positive family history, are elements in favor of the existence of an inherited condition. Extensive and progressive cephalohematomas after delivery are common in hemophilia, and profuse bleeding after umbilical cord fall or circumcision is seen in hypo-fibrinogenemia or congenital factor XIII deficiency. However, these manifestations are also frequent in hemorrhagic disease of the newborn, an acquired pathology of hemostasis due to vitamin K deficiency in the newborn. In some hereditary plasma coagulation disorders, symptoms may start later: for example, hemarthroses characteristic of hemophilia usually do not appear until the third or fourth year of life, while factor XI deficiency may not become evident until surgery is performed. With regard to family history, the absence of positive data does not exclude hereditary coagulopathy: this can happen in hemophilia A (congenital factor VIII deficiency) and is frequent in conditions that are transmitted in an autosomal recessive manner.

Acquired plasma changes can be recognized by their onset at older ages, the negativity of the family history, the lesser severity of bleeding and because the clinical picture is dominated by the manifestations of the underlying disease (for example, liver disease) more than by bleeding. In these acquired coagulopathies, the disorders are usually multiple, involving more than one stage of the hemostasis mechanism, which generally differentiates them from congenital conditions.

It is important to investigate the history of drug ingestion as a cause of acquired coaguiopathy (quantitative and qualitative changes in platelets due to diuretics or anti-inflammatories, respectively, or deficiencies of K factors dependent on surreptitious use of dicumarinics). A careful clinical examination that reveals the existence of liver disease, collagen disease, or neoplasm can clarify the origin of a hemorrhagic picture by guiding us about its probable flsiopathogenesis (decreased synthesis, defective synthesis, inhibitory mechanism, or consumption coagulopathy). This impression will then be confirmed or not by laboratory tests.

Laboratory tests on plasma disorders. The prothrombin time (PT) globally measures the factors of the extrinsic mechanism and the common pathway of hemostasis (VII, X, V, II and fibrinogen). The partial thromboplasmin time (TTP) measures the factors of the intrinsic mechanism and the common pathway (XII, XI, IX, VIII, X, V, II and fibrinogen).

In addition, the level of each of the factors can be determined independently, both from a functional and immunological point of view, as well as the presence of fibrinogen degradation products (PDF). In hereditary coagulopathies due to synthesis deficits, a decrease is found in the functional levels of immunological factors of a single factor (eg, hypofibrinogenemia), while in acquired diseases, the decrease is generalized (eg, liver disease) and compromises to all the factors that are synthesized in the liver, except factor VIII. In both cases the situation is corrected with the addition of normal plasma. In alterations due to faulty synthesis (eg: congenital or acquired dysfibrinogenemias) decrease of the factor is observed when measured by functional methods and normality of the factor when determined by immunological techniques, since it is a qualitative condition. In consumption coagulopathies (disseminated intravascular coagulation), all diminished factors are found, including factor VIII, with platelet disease and increased PFD. And finally, in the alterations by inhibitory mechanism (hemostasis inhibitors), the prolongation found in the global tests (TP and TTP) is not corrected with the addition of normal plasma. with plateletpenia and increased PDF. And finally, in the alterations by inhibitory mechanism (hemostasis inhibitors), the prolongation found in the global tests (TP and TTP) is not corrected with the addition of normal plasma. with plateletpenia and increased PDF. And finally, in the alterations by inhibitory mechanism (hemostasis inhibitors), the prolongation found in the global tests (TP and TTP) is not corrected with the addition of normal plasma.