Nonplatelet Hemostatic Disorders- Types and Clinical Manifestations

What Are Non Platelet Hemostatic Disorders?

Hemostasis is a cascade of pathways that prevent bleeding from an injured site. This mechanism involves four stages such as the constriction of the blood vessels, formation of a platelet plug (primary hemostasis), activation of the clotting pathways (involves clotting factors and mediators), and formation and stabilization of fibrin plug (final clot). Abnormalities in the clotting pathways that do not depend on platelet plug formation are termed nonplatelet hemostatic disorders.

These disorders, which are inherited or acquired, affect secondary hemostatic mechanisms which include clotting activation and fibrin stabilization. Etiologically they include coagulation dysfunction (nonvascular) and also vascular abnormalities of hemostasis. Nonplatelet hemostatic disorders are broadly classified into disorders that enhance coagulation and those that inhibit clotting mechanisms. However, some disorders clinically show both symptoms.

How Are Non Platelet Hemostatic Disorders Classified?

Nonplatelet hemostatic disorders are broadly classified into nonvascular hemostatic disorders and vascular hemostatic disorders depending on the origin of hemostatic dysfunction.

Nonvascular Hemostatic Disorders - These disorders occur primarily due to defective nonvascular components such as clotting factors and mediators of coagulation mechanisms.

• Fibrinogen disorders.

• Deficiencies of Protein C, Protein S, Antithrombin III, and Factor V Leiden

• Hemophilia - Types A and B.

• Deficiencies of clotting factors XI, V, VII, X, and XIII.

Vascular Hemostatic Disorders - These conditions occur due to dysfunction or structural abnormalities in vascular vessels and also harmful mediators synthesized due to defective vasculature.

• Collagen vascular disorders.

• Disseminated intravascular coagulation.

• Abnormal circulating proteins.

• Purpuras.

• Waterhouse-Friderichsen syndrome.

• Wiskott-Aldrich syndrome.

• Thrombotic thrombocytopenic purpura.

• Shwartzman phenomenon.

• Cryoglobulinemia.

• Multiple myeloma.

• Cavernous hemangioma.

This article overviews some of the important nonplatelet hemostatic disorders that are commonly encountered in routine clinical practice.

What Are Fibrinogen Disorders?

Fibrinogen disorders include afibrinogenemia (deficiency of fibrinogen) and dysfibrinogenemia (structural defects). Fibrinogen disorders are both acquired and inherited. Clinically their presentation varies from severe bleeding (afibrinogenemia) to thrombotic complications (dysfibrinogenemia).

Clinical Manifestations

• Acquired fibrinogen deficiency occurs following excessive blood loss during surgeries, trauma, postpartum hemorrhage, hemodilution due to massive fluid transfusions, liver dysfunction, and chemotherapy.

• Hereditary dysfibrinogenemia is usually asymptomatic. Occasionally, episodes of diathesis (excessive bleeding tendency) and thromboembolism are reported.

• Intra-abdominal bleeding.

• The severity of bleeding correlates with fibrinogen levels.

Diagnosis

• Fibrinogen levels are decreased.

• Prothrombin time (PT) and thrombin time (TT) are prolonged.

Treatment

• Plasma fibrinogen is substituted by cryoprecipitate.

• Administration of purified inactivated concentrates of fibrinogen.

What Are Hemophilia A and Hemophilia B?

The hemophilias are bleeding disorders acquired through X-linked inheritance. Deficiency of clotting factor VIII causes hemophilia A and hemophilia B is due to deficiency of factor IX.

Clinical Symptoms

• Recurrent, profuse, excessive bleeding episodes during minor injury, dental extractions or surgeries.

• Hemarthrosis (bleeding in joints).

• Epistaxis (nasal bleeding).

• Gastrointestinal bleeding due to peptic ulcers.

Diagnosis

• Activated partial thrombin time (aPTT) is prolonged.

• Factor VIII activity levels are reduced to 40% below the normal level.

Treatment

• Clotting factor VIII replacement therapy is the standard practice.

• Antifibrinolytic therapy is given for mucosal bleeding.

• Plasma-derived and recombinant concentrates of factor IX are also recommended.

What Are Clotting Inhibiting Disorders?

Coagulation-inhibiting deficiencies are those clotting disorders that are caused due to improper activation or deactivation of certain clotting factors such as Factor X and Factor XIII that are involved in intrinsic and extrinsic clotting pathways.

Factor X Deficiency - It is an inherited disorder (autosomal recessive trait).

• This deficiency is due to defective activation in both intrinsic and extrinsic pathways of clotting mechanisms since activated factor X is an important precursor at the point of convergence of both pathways.

• Prolonged PT and aPTT were recorded in factor X deficiency.

• Acquired Factor X deficiency is seen in light chain–related amyloidosis.

• Treatment includes the administration of plasma-derived concentrate of factor X and prothrombin-complex concentrate.

Factor XIII Deficiency - Factor XIII is an enzyme also known as the fibrin-stabilizing factor (FSF). Absence or defective synthesis of Factor XIII inhibits blood clot formation and leads to hemorrhagic diathesis.

• Factor XIII is present in platelets, monocytes, and plasma.

• Clinically presented as neonatal hemorrhage and recurrent diathesis for lifelong.

• Intracranial hemorrhage and abdominal bleeding are common.

• Acquired deficiency is seen in leukemia, chemotherapy, and erosive colitis.

• Screening tests show normal PT and aPTT. Hence immunoassay for Factor XIII is done as the confirmatory diagnosis.

• Treatment includes prophylactic therapy infusions of Factor XIII concentrate for lifelong.

What Are Collagen Vascular Disorders?

Vascular nonplatelet hemostatic disorders include inherited connective tissue abnormalities and vascular malformations that affect the normal clotting process. These vascular abnormalities are prone to thrombus formation or hemorrhage. Inherited connective tissue (collagen) disorders that have major vascular complications are,

• Marfan Syndrome - Marfan syndrome is caused due to genetic defects resulting in structural abnormality of microfibrils (an extracellular matrix component).

• Ehlers-Danlos Syndrome Type IV - It is caused due to genetic mutation which leads to defective production of type III collagen.

Clinical Symptoms

• Hyperextensible skin.

• Hyperflexible joints.

• Skin fragility.

• Reduced or delayed wound healing.

• Congenital intracranial aneurysms.

• Massive gastrointestinal hemorrhage.

• Cardiac insufficiency.

• Malformations in pulmonary, hepatic, intracerebral, and spinal vascular vessels result in hemorrhage or thrombosis.

Diagnosis and Treatment

• Color duplex ultrasonography detects vascular abnormalities.

• Therapeutic measures include embolization and ligation of the malformations.

What Is Disseminated Intravascular Coagulation?

Disseminated intravascular coagulation (DIC) is a multifactorial syndrome due to the abnormal functioning of factors and mediators involved in clotting mechanisms. It is triggered by excessive use or destruction of these factors within the vessels due to widespread abnormal hemostasis. Clinical conditions that enhance DIC are septic shock, hemorrhage, endotoxin release, and amniotic fluid embolism.

Indications of DIC

• Microthrombi.

• Intravascular bleeding.

• Malignancies.

• Trauma and hemorrhagic shock.

• Aortic aneurysms.

• Burn injuries.

• Hypothermia.

• Incompatible blood transfusions.

Treatment

• Management of the underlying disorders and predisposing risk factors.

• Supportive measures to avoid bleeding complications.

• Administration of cryoprecipitate and fresh frozen plasma (FFP).

• Use of anticoagulants like low molecular weight heparins.

What Are Abnormal Circulating Protein-Associated Disorders?

Abnormal circulating proteins are produced as an inflammatory response during infections, autoimmune reactions, and neoplastic disorders. These abnormal proteins precipitate inside microvasculature and cause localized thrombosis. These abnormalities are categorized under vascular nonplatelet hemostatic disorders. Some of these conditions include;

• Multiple myeloma.

• Cryoglobulinemia.

• Waldenström macroglobulinemia.

Clinical Interventions

• Clinical symptoms such as skin rashes due to purpura (hemorrhagic spots under the skin) and urticaria, polyneuropathy, arthralgia (pain in joints), and glomerulonephritis.

• Laboratory findings show reduced complement levels and abnormal paraprotein and immunoglobulin proportions.

• Management involves treatment of the symptoms such as steroid therapy to lower inflammation and low-dose coagulants to control subcutaneous hemorrhage.

Conclusion

Hemostatic dysfunctions may occur even with normal platelet functioning. These disorders are collectively termed nonplatelet hemostatic disorders. They are clinically manifested with thrombotic events or hemorrhagic episodes depending on the predisposing defects. Extended screening diagnosis and prophylactic preventive measures would favor better outcomes for such unique disorders.