The signs and symptoms of TTP may at first be subtle and nonspecific. Many people experience an influenza-like or diarrheal illness before developing TTP. Neurological symptoms are very common and vary greatly in severity. Frequently reported symptoms include feeling very tired, confusion, and headaches. Seizures and symptoms similar to those of a stroke can also be seen.

As TTP progresses, blood clots form within small blood vessels (microvasculature), and platelets (clotting cells) are consumed. As a result, bruising, and rarely bleeding can occur. The bruising often takes the form of purpura, while the most common site of bleeding, if it occurs, is from the nose or gums. Larger bruises (ecchymoses) may also develop.

The classic presentation of TTP includes a constellation of five medical signs which classically support the clinical diagnosis of TTP, although it is unusual for patients to present with all 5 symptoms. The pentad includes:

- Fever

- Changes in mental status

- Thrombocytopenia

- Reduced kidney function

- Haemolytic anaemia (microangiopathic hemolytic anemia).

High blood pressure (hypertension) may be found on examination.

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of the blood-coagulation system, causing extensive microscopic clots to form in the small blood vessels throughout the body, resulting in low platelet counts. These small blood clots, called thrombi, can damage many organs including the kidneys, heart, brain, and nervous system. In the era before effective treatment with plasma exchange, the fatality rate was about 90%. With plasma exchange, this has dropped to 10% at six months. Because the disease generally results from antibodies that activate the immune system to inhibit the ADAMTS13 enzyme, agents that suppress the immune system, such as glucocorticoids, rituximab, cyclophosphamide, vincristine, or ciclosporin, may also be used if a relapse or recurrence follows plasma exchange. Platelets are not transfused unless the patient has a life-threatening bleed, since the transfused platelets would also quickly be consumed by thrombi formation, leading to a minimal increase in circulating platelets.

Most cases of TTP arise from autoantibody-mediated inhibition of the enzyme ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand factor (vWF) into smaller units. The increase in circulating multimers of vWF increases platelet adhesion to areas of endothelial injury, particularly where arterioles and capillaries meet, which in turn results in the formation of small platelet clots called thrombi. As platelets are used up in the formation of thrombi, this then leads to a decrease in the number of overall circulating platelets, which may then cause life-threatening bleeds. The reason why the antibodies form is generally unknown for most patients, though it can be associated with some medications and autoimmune diseases such as HIV and Lupus, as well as pregnancy.

A rarer form of TTP, called Upshaw–Schulman syndrome, or "Inherited TTP," results from an autosomal recessive gene that leads to ADAMTS13 dysfunction from the time of birth, resulting in persisting large vWF multimers, which in turn results in the formation of thrombi (small platelet clots).

Red blood cells passing the microscopic clots are subjected to shear stress, which damages their membranes, leading to rupture of red blood cells within blood vessels, which in turn leads to anaemia and schistocyte formation. The presence of these blood clots in the small blood vessels reduces blood flow to organs resulting in cellular injury and end organ damage. Current therapy is based on support and plasmapheresis to reduce circulating antibodies against ADAMTS13 and replenish blood levels of the enzyme.

The signs and symptoms in the increasingly rare cases of cryoglobulinemic disease that cannot be attributed to an underlying disease generally resemble those of patients suffering Type II and III (i.e. mixed) cryoglobulinemic disease.

Signs and symptoms due to the cryoglobulins of type I disease reflect the hyperviscosity and deposition of cryoglobulins within the blood vessels which reduce or stop blood perfusion to tissues. These events occur particularly in cases where blood cryoglobulin levels of monoclonal IgM are high in patients with IgM MGUS, smoldering Waldenström's macroglobulinemia, or Waldenström's macroglobulinemia and in uncommon cases where the levels of monoclonal IgA, IgG, free κ light chains, or free λ light chains are extremely high in patients with non-IgM MGUS, non-IgM smoldering multiple myeloma, or multiple myeloma. The interruption of blood flow to neurological tissues can cause symptoms of confusion, headache, hearing loss, and peripheral neuropathy. Interruption of blood flow to other tissues in type I disease can cause cutaneous manifestations of purpura, acrocyanosis, necrosis, ulcers, and livedo reticularis; spontaneous nose bleeds, joint pain, membranoproliferative glomerulonephritis; and cardiovascular disturbances such as shortness of breath, hypoxemia, and congestive heart failure.

A common complaint among patients with cold agglutinin disease is painful fingers and toes with purplish discoloration associated with cold exposure. In chronic cold agglutinin disease, the patient is more symptomatic during the colder months.

Cold agglutinin mediated acrocyanosis differs from Raynaud phenomenon. In Raynaud phenomena, caused by vasospasm, a triphasic color change occurs, from white to blue to red, based on vasculature response. No evidence of such a response exists in cold agglutinin disease.

Other symptoms

- Respiratory symptoms: May be present in patients with "M pneumoniae" infection.

- Hemoglobinuria (the passage of dark urine that contains hemoglobin), A rare symptom that results from hemolysis, this may be reported following prolonged exposure to cold, hemoglobinuria is more commonly seen in paroxysmal cold hemoglobinuria.

- Chronic fatigue, Due to anemia.

Cold autoimmune hemolytic anemia caused by cold-reacting autoantibodies. Autoantibodies that bind to the erythrocyte membrane leading to premature erythrocyte destruction (hemolysis) characterize autoimmune hemolytic anemia.

Vascular disease is a class of diseases of the blood vessels – the arteries and veins of the circulatory system of the body. It is a subgroup of cardiovascular disease. Disorders in this vast network of blood vessels, can cause a range of health problems which can be severe or prove fatal.

Macrovascular disease is a disease of any large ("macro") blood vessels in the body. It is a disease of the large blood vessels, including the coronary arteries, the aorta, and the sizable arteries in the brain and in the limbs.

This sometimes occurs when a person has had diabetes for an extended period of time. Fat and blood clots build up in the large blood vessels and stick to the vessel walls.

Three common macrovascular diseases are coronary disease (in the heart), cerebrovascular disease (in the brain), and peripheral vascular disease (in the limbs)

Macrovascular disease (macroangiopathy) refers to atherosclerosis. Atherosclerosis is a form of arteriosclerosis (thickening and hardening of arterial walls), characterized by plaque deposits of lipids, fibrous connective tissue, calcium, and other blood substances. Atherosclerosis, by definition, affects only medium and large arteries (excluding arterioles).

Macrovascular disease is associated with the development of coronary artery disease, peripheral vascular disease, brain attack (stroke), and increased risk of infection. Type 2 diabetes is more closely associated with macrovascular diseases than type 1 diabetes. Peripheral vascular disease and increased risk of infection have important implications in the care of the acutely ill patient.

Most people do not have symptoms. It can cause a mild to moderate enlargement of the spleen, splenomegaly, as well as hemolytic anemia (which is the form of anemia due to abnormal breakdown of red blood cells prematurely). Too much hemoglobin C can reduce the number and size of red blood cells in the body, causing mild anemia. Occasionally, jaundice may occur. Some persons with this disease may develop gallstones that require treatment. Continued hemolysis may produce pigmented gallstones, an unusual type of gallstone composed of the dark-colored contents of red blood cells.

Target cells, microspherocytes and HbC crystals are found in a blood smear from a homozygous patient.

There are several types of vascular disease, (which is a subgroup of cardiovascular disease), the signs and symptoms depend on which type, among them are:

- Erythromelalgia - a rare peripheral vascular disease where syndromes includes burning pain, increased temperature, erythema and swelling, of mainly the hands and feet are affected.

- Peripheral artery disease – happens when atheromatous plaques build up in the arteries that supply blood to the arms and legs, plaque causes the arteries to narrow or become blocked.

- Renal artery stenosis - is the narrowing of renal arteries that carry blood to the kidneys from the aorta.

- Buerger's disease – is due to small blood vessels that inflame and swell, vessels then narrow or are blocked by blood clots.

- Raynaud's disease – a rare peripheral vascular disorder of constriction of the peripheral blood vessels, in the fingers and toes when the person is cold.

- Disseminated intravascular coagulation – a widespread activation of clotting in the smaller blood vessels.

- Cerebrovascular disease–a group of vascular diseases that affect brain function.

Kyrle disease symptoms are chronic and have an onset during adulthood between the ages of 30 and 50 years of age. However, there were reported cases of early onset as early as 5 years of age and late onset as late as 75 years of age. The main symptom is the development of small papules into painless lesions that are surrounded by silvery scales. The lesions are painless, however, there is a chance that the patient may experience extreme urges to itch them. In time, these lesions grow up to a radius of 0.75 inch and develop into red-brown nodules with a central plug of keratin. As more lesions develop, they can come together and form larger keratotic plaques. These lesions are usually observed on the lower extremities, however, can also develop on the upper extremities, such as, the arms, the head and the neck. The only parts of the body that Kyrle disease do not form are the palms, soles, and mucous membranes. Lesions may heal spontaneously without treatment, however, new ones will develop in its place.

Other symptoms that may be observed:

- Hyperkeratotic cone-shaped papular plugs

- Hyperkeratotic verrucous plaques

- Diabetes mellitus

- Hepatic insufficiency

- Presence of albumin in the urine

- Excess sugar in the urine

Kyrle disease or hyperkeratosis follicularis et parafollicularis in cutem penetrans is identified as a form of an acquired perforating disease. Other major perforating diseases are elastosis perforans serpiginosa and reactive perforating collagenosis. Recently, however, there is a controversy on categorizing Kyrle disease with perforating dermatosis or a subtype of acquired perforating collagenosis.

Kyrle disease was first described by Josef Kyrle in 1916 when a diabetic woman presented generalized hyperkeratotic nodules. The disease is distinguished by large papules with central keratin plus on the skin, usually on the legs of the patient and is often in conjunction with hepatic, renal or diabetic disorders. It can affect both females and males with a 6:1 ratio. The papules usually show up on the patient with an average age of 30 years. Kyrle disease is a rare disease unless there is a high count of patients with chronic renal failure. The disease seems to be more prevalent in African Americans, which can be correlated to the high incidence of diabetes mellitus and renal failure in the population.

The histiocytosis of Rosai–Dorfman disease can occur in lymph nodes, causing lymphadenopathy, or can occur outside lymph nodes in extranodal disease.

Lymphadenopathy can occur in one or more groups of lymph nodes. Among 358 cases of Rosai–Dorfman disease that Rosai collected in a disease registry for which the location of lymphadenopathy was specified, 87.3% had cervical lymphadenopathy. Axillary, inguinal, and mediastinal lymphadenopathy are also found in Rosai–Dorfman disease.

The clinical signs of minimal change disease are proteinuria (abnormal excretion of proteins, mainly albumin, into the urine), oedema (swelling of soft tissues as a consequence of water retention), and hypoalbuminaemia (low serum albumin). These signs are referred to collectively as nephrotic syndrome. Minimal change disease is unique among the causes of nephrotic syndrome as it lacks evidence of pathology in light microscopy, hence the name.

When albumin is excreted in the urine, its serum (blood) concentration decreases. Consequently, the intravascular oncotic pressure reduces relative to the interstitial tissue. The subsequent movement of fluid from the vascular compartment to the interstitial compartment manifests as the soft tissue swelling referred to as oedema. This fluid collects most commonly in the feet and legs, in response to gravity, particularly in those with poorly functioning valves. In severe cases, fluid can shift into the peritoneal cavity (abdomen) and cause ascites. As a result of the excess fluid, individuals with minimal change disease often gain weight, as they are excreting less water in the urine, and experience fatigue. Additionally, the protein in the urine causes it to become frothy.

Kidney complications are a common and serious effect of the disease; kidney insufficiency and kidney failure may worsen throughout life. The presence of protein in the urine (which causes foamy urine) is often the first sign of kidney involvement. End-stage kidney failure in those with Fabry disease typically occurs in the third decade of life, and is a common cause of death due to the disease.

Cardiac complications occur when glycolipids build up in different heart cells; heart-related effects worsen with age and may lead to increased risk of heart disease. High blood pressure and restrictive cardiomyopathy are commonly observed.

Lung involvement is typically in the form of hemoptysis, pleuritis, cough, or fever, and in severe cases can be life-threatening if the outlet pulmonary artery develops an aneurysm which ruptures causing severe vascular collapse and death from bleeding in the lungs. Nodules, consolidations, cavities and ground glass lesions are common in patients with pulmonary involvement. Pulmonary artery thrombosis may occur.

Vascular-related cutaneous conditions result from dysfunction of the blood or blood vessels in the dermis, or lymphatics in the subcutaneous tissues.

- Aagenaes syndrome

- Acroangiodermatitis (acroangiodermatitis of Mali, Mali acroangiodermatitis, Pseudo-Kaposi's sarcoma)

- Acute hemorrhagic edema of infancy (acute hemorrhagic edema of childhood, Finkelstein's disease, infantile postinfectious iris-like purpura and edema, medallion-like purpura, purpura en cocarde avec oedema, Seidlmayer syndrome)

- Arterial insufficiency ulcer (ischemic ulcer)

- Arteriosclerosis obliterans

- Bier spots

- Blueberry muffin baby

- Bonnet–Dechaume–Blanc syndrome (Wyburn–Mason syndrome)

- Bullous lymphedema

- Bullous small vessel vasculitis (bullous variant of small vessel vasculitis)

- Calciphylaxis

- Caput succedaneum

- Cholesterol embolus (warfarin blue toe syndrome)

- Cobb syndrome

- Corona phlebectatica

- Cryofibrinogenemic purpura

- Cryoglobulinemic purpura

- Cryoglobulinemic vasculitis

- Cutaneous small-vessel vasculitis (cutaneous leukocytoclastic angiitis, cutaneous leukocytoclastic vasculitis, cutaneous necrotizing venulitis, hypersensitivity angiitis)

- Deep venous thrombosis

- Disseminated intravascular coagulation

- Doucas and Kapetanakis pigmented purpura

- Drug-induced purpura

- Drug-induced thrombocytopenic purpura

- Eczematid-like purpura of Doucas and Kapetanakis

- Epidemic dropsy

- Erythema elevatum diutinum

- Erythromelalgia (acromelalgia, erythermalgia)

- Factitial lymphedema (hysterical edema)

- Fibrinolysis syndrome (defibrinating syndrome, hypofibrinogenemia)

- Food-induced purpura

- Generalized essential telangiectasia (general essential telangiectasia)

- Giant-cell arteritis

- Gougerot–Blum syndrome (pigmented purpuric lichenoid dermatitis, pigmented purpuric lichenoid dermatitis of Gougerot and Blum)

- Harlequin color change

- Hematopoietic ulcer

- Hennekam syndrome (Hennekam lymphangiectasia-lymphedema syndrome, intestinal lymphagiectasia-lymphedema-mental retardation syndrome)

- Henoch–Schönlein purpura (anaphylactoid purpura, purpura rheumatica, Schönlein–Henoch purpura)

- Hereditary hemorrhagic telangiectasia (Osler's disease, Osler–Weber–Rendu disease)

- Idiopathic thrombocytopenic purpura (autoimmune thrombocytopenic purpura, Werlhof's disease)

- IgA vasculitis

- Kawasaki's disease (mucocutaneous lymph node syndrome)

- Levamisole-induced vasculitis

- Lichen aureus (lichen purpuricus)

- Livedo racemosa

- Livedo reticularis

- Livedoid dermatitis (embolia cutis medicamentosa, Nicolau syndrome)

- Livedoid vasculopathy (atrophie blanche, livedo reticularis with summer ulceration, livedoid vasculitis, PURPLE syndrome, segmental hyalinizing vasculitis)

- Lymphedema praecox

- Lymphedema–distichiasis syndrome

- Maffucci syndrome

- Majocchi's disease (purpura annularis telangiectodes, purpura annularis telangiectodes of Majocchi)

- Malignant atrophic papulosis (Degos' disease)

- Marshall–White syndrome

- Meige lymphedema

- Microscopic polyangiitis (microscopic polyarteritis, microscopic polyarteritis nodosa)

- Mondor's disease (Mondor's syndrome of superficial thrombophlebitis)

- Neuropathic ulcer (mal perforans)

- Njolstad syndrome

- Nonne–Milroy–Meige syndrome (hereditary lymphedema, Milroy disease)

- Obstructive purpura

- Orthostatic purpura (stasis purpura)

- Painful bruising syndrome (autoerythrocyte sensitization, Gardner–Diamond syndrome, psychogenic purpura)

- Parkes Weber syndrome

- Paroxysmal hand hematoma (Achenbach syndrome)

- Paroxysmal nocturnal hemoglobinuria

- Polyarteritis nodosa (panarteritis nodosa, periarteritis nodosa)

- Postcardiotomy syndrome

- Perinatal gangrene of the buttock

- Pigmentary purpuric eruptions (progressive pigmentary dermatosis, progressive pigmenting purpura, purpura pigmentosa chronica)

- Postinflammatory lymphedema

- Postmastectomy lymphangiosarcoma (Stewart–Treves syndrome)

- Purpura fulminans (purpura gangrenosa)

- Purpura secondary to clotting disorders

- Purpuric agave dermatitis

- Raynaud phenomenon

- Raynaud's disease (primary Raynaud's phenomenon)

- Reactive angioendotheliomatosis

- Schamberg's disease (progressive pigmentary dermatosis of Schamberg, purpura pigmentosa progressiva, Schamberg's purpura)

- Secondary lymphedema

- Septic thrombophlebitis

- Sinusoidal hemangioma

- Sneddon's syndrome (idiopathic livedo reticularis with cerebrovascular accidents)

- Solar purpura (actinic purpura, senile purpura)

- Stasis dermatitis (congestion eczema, gravitational dermatitis, gravitational eczema, stasis eczema, varicose eczema)

- Superficial thrombophlebitis

- Takayasu arteritis (aortic arch syndrome, pulseless disease)

- Temporal arteritis (cranial arteritis, Horton's disease)

- Thromboangiitis obliterans (Buerger's disease)

- Thrombotic thrombocytopenic purpura (Moschcowitz syndrome)

- Traumatic purpura

- Trousseau's syndrome

- Unilateral nevoid telangiectasia (nevoid telangiectasia)

- Urticarial vasculitis (chronic urticaria as a manifestation of venulitis, hypocomplementemic urticarial vasculitis syndrome, hypocomplementemic vasculitis, unusual lupus-like syndrome)

- Venous insufficiency ulceration

- Waldenström hyperglobulinemic purpura (purpura hyperglobulinemica)

- Waldenström macroglobulinemia

- Wegener granulomatosis

- Yellow nail syndrome (primary lymphedema associated with yellow nails and pleural effusion)

CNS involvement most often occurs as a chronic meningoencephalitis. Lesions tend to occur in the brainstem, the basal ganglia and deep hemispheric white matter and may resemble those of MS. Brainstem atrophy is seen in chronic cases.

Neurological involvements range from aseptic meningitis to vascular thrombosis such as dural sinus thrombosis and organic brain syndrome manifesting with confusion, seizures, and memory loss. Sudden hearing loss (Sensorineural) is often associated with it. They often appear late in the progression of the disease but are associated with a poor prognosis.

Although the dermatological changes are the most obvious symptoms of Urbach–Wiethe disease, many patients also have neurological symptoms. About 50–75% of the diagnosed cases of Urbach–Wiethe disease also show bilateral symmetrical calcifications on the medial temporal lobes. These calcifications often affect the amygdala and the periamygdaloid gyri. The amygdala is thought to be involved in processing biologically relevant stimuli and in emotional long term memory, particularly those associated with fear, and both PET and MRI scans have shown a correlation between amygdala activation and episodic memory for strongly emotional stimuli. Therefore, Urbach–Wiethe disease patients with calcifications and lesions in these regions may suffer impairments in these systems. These calcifications are the result of a buildup of calcium deposits in the blood vessels within this brain region. Over time, these vessels harden and the tissue they are a part of dies, causing lesions. The amount of calcification is often related to disease duration. The true prevalence of these calcifications is difficult to accurately state as not all patients undergo brain imaging. Some patients also exhibit epilepsy and neuropsychiatric abnormalities. Epilepsy symptoms could begin with light anxiety attacks and it can be controlled with "Epilum" (Epilepsy Medicine) Other patients present with symptoms similar to schizophrenia while some suffer from mood, anxiety, and psychotic disorders.

The most common presentation of Milroy Disease is bilateral lower extremity lymphedema, and may also be accompanied by hydrocele.

Minimal change disease (also known as MCD and nil disease, among others) is a disease affecting the kidneys which causes a nephrotic syndrome. Nephrotic syndrome leads to the excretion of protein, which causes the widespread oedema (soft tissue swelling) and impaired kidney function commonly experienced by those affected by the disease. It is most common in children and has a peak incidence at 2 to 3 years of age.

Farber disease (also known as Farber's lipogranulomatosis, ceramidase deficiency, "Fibrocytic dysmucopolysaccharidosis," and "Lipogranulomatosis") is an extremely rare (80 cases reported worldwide to this day) autosomal recessive lysosomal storage disease marked by a deficiency in the enzyme ceramidase that causes an accumulation of fatty material sphingolipids leading to abnormalities in the joints, liver, throat, tissues and central nervous system. Normally, the enzyme ceramidase breaks down fatty material in the body’s cells. In Farber Disease, the gene responsible for making this enzyme is mutated. Hence, the fatty material is never broken down and, instead, accumulates in various parts of the body, leading to the signs and symptoms of this disorder.